Heterocyclic TRPV1 receptor ligands

ABSTRACT

The invention relates to compounds of formulae I(a)-I(d): 
                         
and pharmaceutically acceptable derivatives thereof, compositions comprising an effective amount of a compound of formulae I(a)-I(d) or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, UI, an ulcer, IBD and IBS, comprising administering to an animal in need thereof an effective amount of a compound of formulae I(a)-I(d) or a pharmaceutically acceptable derivative thereof.

This application claims the benefit of U.S. provisional application No.61/108,414, filed Oct. 24, 2008, the disclosure of which is incorporatedby reference herein in its entirety.

1. FIELD OF THE INVENTION

The invention relates to novel compounds, pharmaceutically acceptablederivatives thereof, compositions thereof and methods for treating orpreventing a condition such as pain comprising administering to ananimal said compounds and compositions.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for three months or longer and canlead to significant changes in a patient's personality, lifestyle,functional ability and overall quality of life (K. M. Foley, Pain, inCecil Textbook of Medicine 100-107 (J. C. Bennett and F. Plum, Eds.,20th Ed. 1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or central nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at vanilloid receptors to painprocessing (V. Di Marzo et al., Current Opinions in Neurobiology,12:372-379 (2002)).

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. K. M.Foley, Pain, in Cecil Textbook of Medicine 100-107 (J. C. Bennett and F.Plum, Eds., 20th Ed. 1996). In addition to the above-listed treatments,neuropathic pain, which can be difficult to treat, has also been treatedwith anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid,topiramate, phenyloin), NMDA antagonists (e.g., ketamine,dextromethorphan), topical lidocaine (for post-herpetic neuralgia), andtricyclic antidepressants (e.g., fluoxetine, sertraline andamitriptyline).

Urinary incontinence (“UI”) is uncontrollable urination, generallycaused by bladder-detrusor-muscle instability. UI affects people of allages and levels of physical health, both in health care settings and inthe community at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle over activity.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority starts between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow, Ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered.

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more women than men. In IBS, stimulisuch as stress, diet, drugs, hormones, or irritants can cause thegastrointestinal tract to contract abnormally. During an episode of IBS,contractions of the gastrointestinal tract become stronger and morefrequent, resulting in the rapid transit of food and feces through thesmall intestine, often leading to diarrhea. Cramps result from thestrong contractions of the large intestine and increased sensitivity ofpain receptors in the large intestine.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow, Ed., 1997).

U.S. Patent Application Publication No. US 2009/0170868 A1 by Tafessedescribes TRPV1 antagonists and use thereof.

U.S. Patent Application Publication No. US 2005/0165032 A1 by Norman etal. and International PCT Publication No. WO 2005/070929 describevanilloid receptor ligands and their use in treating pain.

U.S. Patent Application Publication No. US 2006/0229307 A1 by Blurton etal. and International PCT Publication No. WO 2004/099177 describesubstituted 1-phthalazinamines as VR-1 antagonists.

U.S. Patent Application Publication No. US 2004/0156869 A1 byBakthavatchalam et al. and International PCT Publication No. WO2004/055004 describe carboxylic acid, phosphate or phosphonatesubstituted quinazolin-4-ylamine analogues as capsaicin receptormodulators.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, UI, an ulcer, IBD, and IBS. Citation of anyreference in the Background of the Invention Section of this applicationis not to be construed as an admission that such reference is prior artto the present application.

3. SUMMARY OF THE INVENTION

The invention encompasses compounds of formulae I(a), I(b), I(c) andI(d):

or a pharmaceutically acceptable derivative thereof, where

each W is independently N or C(R₃) and each B is independently N(R₃),C(═O), C(═S) or C(R₃)₂, provided that when a W group is N then no saidnitrogen atom can be connected to 2 or more nitrogen atoms;

U is selected from —OAr₂, —N(R₂₀)Ar₂, —SAr₂, —S(═O)Ar₂, and —S(═O)₂Ar₂;

Ar₁ is:

provided that when Ar₁ is connected to the 7-position of a5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl, then R₂ isnot —CH₂OH;

Ar₂ is:

c is the integer 0, 1, or 2;

Y₁, Y₂, and each Y₃ are independently selected from —C(R₂₀)₂—, —N(R₂₁)—,and —O—, where no more than one of Y₁, Y₂, and Y₃ can be O and no morethan a total of two (C₁-C₆)alkyl groups are substituted on all of Y₁,Y₂, and Y₃;

R_(12a) and R_(12b) are each independently selected from —H and—(C₁-C₆)alkyl;

E is ═O, ═S, ═CH(C₁-C₆)alkyl, ═CH(C₂-C₆)alkenyl, —NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, —(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl; or    -   (b) a group of formula Q, where Q is:

each Z₁ is independently selected from —H, —SR₇, —CH₂OR₇, —CH₂SR₇,—CH₂N(R₂₀)₂, and -halo;

each Z₂ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CH₂OR₇, -phenyl, and -halo;

each Z₃ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, and -phenyl;

each Z₄ is independently selected from —H, —OH, —OR₂₀, —(C₁-C₆)alkyl,and —N(R₂₀)₂;

each J is independently selected from —OR₂₀, —SR₂₀, —N(R₂₀)₂, and —CN;

provided that at least one R₂ group is a group of formula Q;

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) —C(═NR₂₈)N(R₂₈)₂, —OC(═O)N(R₂₈)₂, —OC(═O)N(R₂₈)S(═O)₂R₂₈,        —O(C₁-C₆)alkyl-N(R₂₈)₂, —O(C₁-C₆)alkyl-OR₂₈,        —S(═O)₂N(R₂₈)C(═O)R₂₈, —S(═O)₂N(R₂₈)C(═O)OR₂₈,        —S(═O)₂N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═O)OR₂₈,        —N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═NR₂₈)N(R₂₈)₂, —N(R₂₈)S(═O)₂R₂₈,        —N(R₂₈)S(═O)₂N(R₂₈)₂, —N(R₂₈)(C₁-C₆)alkyl-NR₂₈)₂,        —N(R₂₈)(C₁-C₆)alkyl-OR₂₈, or —(C₁-C₆)alkyl-R₂₂; or    -   (c) a group of the formula —R₂₃-M-A-R₂₄; or    -   (d) two R₃ groups together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups, and which bridge optionally contains —HC═CH—        within the (C₂-C₆)bridge; or    -   (e) two R₃ groups together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(═O)—R_(c),—(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(═O)₂—N(═O)₂, or —(CH₂)₂—N(R_(c))S(═O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        optionally substituted with 1, 2 or 3 independently selected R₇        groups;

each R_(c) is independently —H or —(C₁-C₄)alkyl;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, —C(═O)—(C₁-C₆)alkyl, or —C(═O)N(R₂₀)₂;

each R₈ and R₉ is independently:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, or -phenyl, each of        which is optionally substituted with 1 or 2-OH groups; or    -   (b) —H, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo),        —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —SC(halo)₃, —SCH(halo)₂,        —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,        —N(R₇)₂, —NR₇OH, —OR₇, —C(═O)OR₇, —C(═O)OR₇, —OC(═O)R₇,        —OC(═O)OR₇, —SR₇, —S(═O)R₇, or —S(═O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —C(═O)R₇, —C(═O)OR₇,—OC(═O)R₇, or —OC(═O)OR₇;

each R₁₄ is independently:

-   -   (a) —H, —CN, —OH, -halo, —N₃, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), -(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl,        —(C₂-C₆)haloalkenyl, —(C₂-C₆)haloalkynyl,        —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)alkoxy-(C₂-C₆)alkenyl,        —(C₁-C₆)alkoxy-(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyl,        —OC(halo)₃, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —O(CH₂)_(b)OR₇,        —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂, —N(R₇)(CH₂)_(b)OR₇,        —N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂, —N(R₇)C(═O)R₇,        —C(═O)R₇, —(C₁-C₆)alkyl-C(═O)OR₇, —C(═O)OR₇, —OC(═O)R₇,        —OC(═O)OR₇, (═O)R₇, —S(═O)₂R₇, —S(═O)₂N(R₇)₂, —S(═O)₂C(halo)₃,        —S(═O)₂(3- to 7-membered)heterocycle, —C(═O)N(R₇)₂,        —(C₁-C₆)alkyl-C═NOR₇, —(C₁-C₆)alkyl-C(═O)—N(R₇)₂,        —(C₁-C₆)alkyl-NHS(═O)₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₀ groups; or    -   (c) a group of formula —R₃₀—R₃₁—R₃₂;

each R₂₀ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl;

each R₂₁ is independently —H, —(C₁-C₆)alkyl,

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, —C(═O)NH₂, and —C(═O)OR₇;        or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₈)alkanoyl, —(C₁-C₈)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, -phenyl(C₁-C₆)alkyl,        -phenoxy, -phenyl-(C₁-C₆)alkoxy, —NH(C₁-C₆)alkyl,        —NH(C₁-C₆)alkyl)₂, —(S(═O)₂)—(C₁-C₆)alkyl, -(5- to        10-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to        10-membered)bicycloheterocycle, —(C₁-C₁₀)alkyl-(5- to        10-membered)heteroaryl, —(C₁-C₁₀)alkyl-(3- to        7-membered)heterocycle, —(C₁-C₁₀)alkyl-(7- to        10-membered)bicycloheterocycle, —P(═O)(OR_(W))₂ and        —OP(═O)(OR_(W))₂, each of which is optionally substituted with        1, 2 or 3 independently selected R₅ groups;

each R_(W) is independently selected from —H, —(C₁-C₆)alkyl, -phenyl,—(C₁-C₆)alkyl-phenyl, —(C₁-C₁₀)alkyl-(5- to 10-membered)heteroaryl,—(C₁-C₁₀)alkyl-(3- to 7-membered)heterocycle, and —(C₁-C₁₀)alkyl-(7- to10-membered)bicycloheterocycle;

each R₅ is independently:

-   -   (a) —OH, -halo, —NH₂, —C(═O)NH₂, —CN, —NO₂, or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₈)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)hydroxyalkyl,        —(C₁-C₆)haloalkyl, -phenyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)₂alkyl)₂,        —(S(═O)₂)(C₁-C₆)alkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        —(C₁-C₆)alkyl-phenyl, —(C₁-C₁₀)alkyl-(5- to        10-membered)heteroaryl, —(C₁-C₁₀)alkyl-(3- to        7-membered)heterocycle, or —(C₁-C₁₀)alkyl-(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₁₄ groups;

each M is independently a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—OC(═O)—, —C(═O)O—, —O—C(═O)O—, —C(═O)N(R₂₅)—, —N(R₂₅)C(═O)—,—N(R₂₅)S(═O)₂—, —S(═O)₂N(R₂₅)—, —N(R₂₅)—, —OP(═O)(OR₂₅)—,—(R₂₅O)P(═O)(═O)—, —(R₂₅O)P(═O)—, —P(═O)(OR₂₅)—, —OP(═O)₂(OR₂₅)—,—(R₂₅O)P(═O)₂(═O)—, —(R₂₅O)P(═O)₂—, or —P(═O)₂(OR₂₅)—;

each A is independently a bond or —(C₁-C₆)alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R₂₂ groups;

each R₂₃ is independently:

-   -   (a) a bond; or    -   (b) —(C₁-C₆)alkyl-, —(C₂-C₁₀)alkenyl-, or —(C₂-C₁₀)alkynyl-,        each of which is optionally substituted with        -   (i) 1, 2 or 3 independently selected R₂₂ groups; or        -   (ii) 1 or 2 substituents independently selected from —OH and            —(C₁-C₆)alkyl which is optionally substituted with 1 or 2            independently selected R₂₂ groups; or        -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, or R₂₃, R₂₄            and R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to            10-membered)heteroaryl, (3- to 7-membered)heterocycle, or            (7- to 10-membered)bicycloheterocycle, each of which is            optionally substituted with 1, 2, 3, 4, 5 or 6 independently            selected R₂₂ groups;

R₂₄ and R₂₅ are each independently:

-   -   (a) —H or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₁-C₈)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkoxy,        —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —OR₂₅, —(C₃-C₁₀)cycloalkyl,        -phenyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, R₂₄ and R₂₅        together, or R₂₃, R₂₄ and R₂₅ together form a        (C₃-C₁₀)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to        7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5 or 6 independently selected R₂₂        groups;

each R₂₈ is independently:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, or -benzyl, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from -halo, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —O(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₄)alkyl, and —NH(C₁-C₄)alkyl)₂;

each R₃₀ is independently —O—, —NH—, or —S—;

each R₃₁ is independently —C(═O)— or —(C₁-C₆)alkyl which isunsubstituted or substituted with an oxo group;

each R₃₂ is independently —OR₃₃, —C(═O)OR₃₃, —SR₃₃, or —N(R₃₄)₂;

each R₃₃ is independently —H, —P(═O)(OH)₂, —P(═O)(OH)(O(C₁-C₆)alkyl),—P(═O)(C₁-C₆)alkyl)₂, —(C₁-C₆)alkyl, or —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,where the portion of each R₃₃ moiety comprising alkyl is optionallysubstituted with 1, 2 or 3 independently selected R₈ groups;

each R₃₄ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₁₀)alkynyl,        each of which is optionally substituted with 1, 2 or 3        independently selected R₈ groups; or    -   (b) two geminal R₃₄ groups together form a (3- to        7-membered)heterocycle that is optionally substituted with 1, 2        or 3 independently selected R₈ groups;

each -halo is independently —F, —Cl, —Br, or —I;

n is the integer 1, 2 or 3;

p is the integer 1 or 2;

each b is independently selected from the integers 1 and 2;

q is the integer 0, 1, 2, 3 or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2 or 3.

Compounds of formulae I(a), I(b), I(c) and I(d) are believed to behighly soluble in aqueous solutions, e.g., at a pH of about 6.8 and/orat a pH of about 1.2, and are believed to be very potent at the TRPV1receptor.

A compound of formulae I(a), I(b), I(c) or I(d), or a pharmaceuticallyacceptable derivative thereof, is believed to be useful for treating orpreventing pain, UI, an ulcer, IBD, or IBS (each being a “Condition”) inan animal.

The invention also relates to compositions comprising an effectiveamount of a compound of formula I(a), I(b), I(c) or I(d), or apharmaceutically acceptable derivative thereof, and a pharmaceuticallyacceptable carrier or excipient. The compositions are believed to beuseful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Conditioncomprising administering to an animal in need thereof an effectiveamount of a compound of formula I(a), I(b), I(c) or I(d), or apharmaceutically acceptable derivative thereof.

The invention further relates to methods for preventing a Conditioncomprising administering to an animal in need thereof an effectiveamount of a compound of formula I(a), I(b), I(c) or I(d), or apharmaceutically acceptable derivative thereof.

The invention further relates to use of a compound of formula I(a),I(b), I(c) or I(d) in the manufacture of a medicament for treatingand/or preventing a Condition.

The invention still further relates to methods for inhibiting TransientReceptor Potential Vanilloid 1 (“TRPV1,” formerly known as VanilloidReceptor 1 or VR1) function in a cell, comprising contacting a cellcapable of expressing TRPV1 with an effective amount of a compound offormula I(a), I(b), I(c) or I(d), or a pharmaceutically acceptablederivative thereof.

The invention still further relates to a method for preparing acomposition comprising the step of admixing a compound of formula I(a),I(b), I(c) or I(d), or a pharmaceutically acceptable derivative thereof,and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a compound of formula I(a), I(b), I(c)or I(d), or a pharmaceutically acceptable derivative thereof.

The invention still further relates to a compound of formula I(a), I(b),I(c) or I(d), or a pharmaceutically acceptable derivative thereof, foruse as a medicament.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION

The invention includes the following:

(1) A compound or a pharmaceutically acceptable derivative thereof,selected from:

wherein each W is independently N or C(R₃) and each B is independentlyN(R₃), C(═O), C(═S) or C(R₃)₂, provided that when a W group is N then nosaid nitrogen atom can be connected to 2 or more nitrogen atoms;

U is selected from —OAr₂, —N(R₂₀)Ar₂, —SAr₂, —S(═O)Ar₂, and —S(═O)₂Ar₂;

Ar₁ is:

provided that when Ar₁ is connected to the 7-position of a5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl, then R₂ isnot —CH₂OH;

Ar₂ is:

c is the integer 0, 1, or 2;

Y₁, Y₂, and each Y₃ are independently selected from —C(R₂₀)₂—, —N(R₂₁)—,and —O—, wherein no more than one of Y₁, Y₂, and Y₃ can be O and no morethan a total of two (C₁-C₆)alkyl groups are substituted on all of Y₁,Y₂, and Y₃;

R_(12a) and R_(12b) are each independently selected from —H and—(C₁-C₆)alkyl;

E is ═O, ═S, ═CH(C₁-C₆)alkyl, ═CH(C₂-C₆)alkenyl, —NH(C₁-C₆)alkyl, or═N—OR₂₀;

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

each R₂ is independently:

-   -   (a) -halo, —OH, —O(C₁-C₄)alkyl, —CN, —NO₂, —NH₂, —(C₁-C₁₀)alkyl,        —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, or -phenyl; or    -   (b) a group of formula Q, wherein Q is:

each Z₁ is independently selected from —H, —OR₇, —SR₇, —CH₂OR₇, —CH₂SR₇,—CH₂N(R₂₀)₂, and -halo;

each Z₂ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CH₂OR₇, -phenyl, and -halo;

each Z₃ is independently selected from —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, and -phenyl;

each Z₄ is independently selected from —H, —OH, —OR₂₀, —(C₁-C₆)alkyl,and —N(R₂₀)₂;

each J is independently selected from —OR₂₀, —SR₂₀, —N(R₂₀)₂, and —CN;

provided that at least one R₂ group is a group of formula Q;

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) —C(═NR₂₈)N(R₂₈)₂, —OC(═O)N(R₂₈)₂, —OC(═O)N(R₂₈)S(═O)₂R₂₈,        —O(C₁-C₆)alkyl-N(R₂₈)₂, —O(C₁-C₆)alkyl-OR₂₈,        —S(═O)₂N(R₂₈)C(═O)R₂₈, —S(═O)₂N(R₂₈)C(═O)OR₂₈,        —S(═O)₂N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═O)OR₂₈, —N(R₂₈)C(═O)NR₂₈)₂,        —N(R₂₈)C(═NR₂₈)N(R₂₈)₂, —N(R₂₈)S(═O)₂R₂₈, —N(R₂₈)S(═O)₂N(R₂₈)₂,        —N(R₂₈)(C₁-C₆)alkyl-N(R₂₈)₂, —N(R₂₈)(C₁-C₆)alkyl-OR₂₈, or        —(C₁-C₆)alkyl-R₂₂; or    -   (c) a group of the formula —R₂₃-M-A-R₂₄; or    -   (d) two R₃ groups together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2 or 3 independently        selected R₈ groups, and which bridge optionally contains —HC═CH—        within the (C₂-C₆)bridge; or    -   (e) two R₃ groups together form a —CH₂—N(R_(a))—CH₂— bridge, a

bridge, or a

bridge;

R_(a) is —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, —CH₂—C(═O)—R_(c),—(CH₂)—C(═O)—OR_(c), —(CH₂)—C(═O)—N(R_(c))₂, —(CH₂)₂—O—R_(c),—(CH₂)₂—S(═O)₂—N(R_(c))₂, or —(CH₂)₂—N(R_(c))S(═O)₂—R_(c);

R_(b) is:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, -(3- to        7-membered)heterocycle, —N(R_(c))₂, —N(R_(c))—(C₃-C₈)cycloalkyl,        or —N(R_(c))-(3- to 7-membered)heterocycle; or    -   (b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R_(c))-phenyl, or        —N(R_(c))-(5- to 10-membered)heteroaryl, each of which is        optionally substituted with 1, 2 or 3 independently selected R₇        groups;

each R_(c) is independently —H or —(C₁-C₄)alkyl;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₃)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, —C(═O)—(C₁-C₆)alkyl, or —C(═O)N(R₂₀)₂;

each R₈ and R₉ is independently:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, or -phenyl, each of        which is optionally substituted with 1 or 2-OH groups; or    -   (b) —H, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo),        —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —SC(halo)₃, —SCH(halo)₂,        —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,        —N(R₇)₂, —NR₇OH, —OR₇, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —OC(═O)OR₇, —SR₇, —S(═O)R₇, or —S(═O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(═O)R₇, —C(═O)OR₇,—OC(═O)R₇, or —OC(═O)OR₇;

each R₁₄ is independently:

-   -   (a) —H, —CN, —OH, -halo, —N₃, or NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), -(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl,        —(C₂-C₆)haloalkenyl, —(C₂-C₆)haloalkynyl,        —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)alkoxy-(C₂-C₆)alkenyl,        —(C₁-C₆)alkoxy-(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyl,        —OC(halo)₃, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,        —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂,        —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂,        —N(R₇)C(═O)R₇, —C(═O)R₇, —(C₁-C₆)alkyl-C(═O)OR₇, —C(═O)OR₇,        —OC(═O)R₇, —OC(═O)OR₇, —S(═O)R₇, —S(═O)₂R₇, —S(═O)₂N(R₇)₂,        —S(═O)₂C(halo)₃, —S(═O)₂(3- to 7-membered)heterocycle,        —C(═O)N(R₇)₂, —(C₁-C₆)alkyl-C═NOR₇, —(C₁-C₆)alkyl-C(═O)—N(R₇)₂,        —(C₁-C₆)alkyl-NHS(═O)₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₀ groups; or    -   (c) a group of formula —R₃₀—R₃₁—R₃₂;

each R₂₀ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl;

each R₂₁ is independently —H, —(C₁-C₆)alkyl,

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, —C(═O)NH₂, and —C(═O)OR₇;        or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₈)alkanoyl, —(C₁-C₈)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, -phenyl(C₁-C₆)alkyl,        -phenoxy, -phenyl-(C₁-C₆)alkoxy, —NH(C₁-C₆)alkyl,        —N((C₁-C₆)alkyl)₂, —(S(═O)₂)—(C₁-C₆)alkyl, -(5- to        10-membered)heteroaryl, -(3- to 7-membered)heterocycle, -(7- to        10-membered)bicycloheterocycle, —(C₁-C₁₀)alkyl-(5- to        10-membered)heteroaryl, —(C₁-C₁₀)alkyl-(3- to        7-membered)heterocycle, —(C₁-C₁₀)alkyl-(7- to        10-membered)bicycloheterocycle, —P(═O)(OR_(W))₂, and        —OP(═O)(OR_(W))₂, each of which is optionally substituted with        1, 2 or 3 independently selected R₅ groups;

each R_(W) is independently selected from —H, —(C₁-C₆)alkyl, -phenyl,—(C₁-C₆)alkyl-phenyl, —(C₁-C₁₀)alkyl-(5- to 10-membered)heteroaryl,—(C₁-C₁₀)alkyl-(3- to 7-membered)heterocycle, and —(C₁-C₁₀)alkyl-(7- to10-membered)bicycloheterocycle;

each R₅ is independently:

-   -   (a) —OH, -halo, —NH₂, —C(═O)NH₂, —CN, —NO₂, or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₈)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)hydroxyalkyl,        —(C₁-C₆)haloalkyl, -phenyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)₂alkyl)₂,        —(S(═O)₂)(C₁-C₆)alkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,        —(C₁-C₆)alkyl-phenyl, —(C₁-C₁₀)alkyl-(5- to        10-membered)heteroaryl, —(C₁-C₁₀)alkyl-(3- to        7-membered)heterocycle, or —(C₁-C₁₀)alkyl-(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₁₄ groups;

each M is independently a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—OC(═O)—, —C(═O)O—, —O—C(═O)O—, —C(═O)N(R₂₅)—, —N(R₂₅)C(═O)—,—N(R₂₅)S(═O)₂—, —S(═O)₂N(R₂₅)—, —N(R₂₅)—, —OP(═O)(OR₂₅)—,—(R₂₅O)P(═O)(═O)—, —(R₂₅O)P(═O)—, —P(═O)(OR₂₅)—, —OP(═O)₂(OR₂₅)—,—(R₂₅O)P(═O)₂(═O)—, —(R₂₅O)P(═O)₂—, or —P(═O)₂(OR₂₅)—;

each A is independently a bond or —(C₁-C₆)alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R₂₂ groups;

each R₂₃ is independently:

-   -   (a) a bond; or    -   (b) —(C₂-C₁₀)alkenyl-, or —(C₂-C₁₀)alkynyl-, each of which is        optionally substituted with        -   (i) 1, 2 or 3 independently selected R₂₂ groups; or        -   (ii) 1 or 2 substituents independently selected from —OH and            —(C₁-C₆)alkyl which is optionally substituted with 1 or 2            independently selected R₂₂ groups; or        -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, or R₂₃, R₂₄            and R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to            10-membered)heteroaryl, (3- to 7-membered)heterocycle, or            (7- to 10-membered)bicycloheterocycle, each of which is            optionally substituted with 1, 2, 3, 4, 5 or 6 independently            selected R₂₂ groups;

R₂₄ and R₂₅ are each independently:

-   -   (a) —H or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₁-C₈)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkoxy,        —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —OR₂₅, —(C₃-C₁₀)cycloalkyl,        -phenyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, R₂₄ and R₂₅        together, or R₂₃, R₂₄ and R₂₅ together form a        (C₃-C₁₀)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to        7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5 or 6 independently selected R₂₂        groups;

each R₂₈ is independently:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, or -benzyl, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from -halo, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —O(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₄)alkyl, and —N((C₁-C₄)alkyl)₂;

each R₃₀ is independently —O—, —NH—, or —S—;

each R₃₁ is independently —C(═O)— or —(C₁-C₆)alkyl which isunsubstituted or substituted with an oxo group;

each R₃₂ is independently —OR₃₃, —C(═O)OR₃₃, —SR₃₃, or —N(R₃₄)₂;

each R₃₃ is independently —H, —P(═O)(OH)₂, —P(═O)(OH)(O(C₁-C₆)alkyl),—P(═O)(O(C₁-C₆)alkyl)₂, —(C₁-C₆)alkyl, or —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,wherein the portion of each R₃₃ moiety comprising alkyl is optionallysubstituted with 1, 2 or 3 independently selected R₈ groups;

each R₃₄ is independently:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₁₀)alkynyl,        each of which is optionally substituted with 1, 2 or 3        independently selected R₈ groups; or    -   (b) two geminal R₃₄ groups together form a (3- to        7-membered)heterocycle that is optionally substituted with 1, 2        or 3 independently selected R₈ groups;

each -halo is independently —F, —Br, or —I;

n is the integer 1, 2 or 3;

p is the integer 1 or 2;

each b is independently selected from the integers 1 and 2;

q is the integer 0, 1, 2, 3 or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6;

s is the integer 0, 1, 2, 3, 4, or 5; and

t is the integer 0, 1, 2 or 3.

(2) The compound of (1), wherein Ar₁ is:

(3) The compound of (2), wherein R₂ is in the para-position with respectto the point of attachment of Ar₁ to the fused rings of I(a), I(b), I(c)or I(d).

(4) The compound of any one of (1) to (3), wherein R₁ is selected from-halo, —(C₁-C₄)alkyl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo) andpreferably is selected from -halo, —CH₃ or —C(halo)₃.

(5) The compound of any one of (1) to (4), wherein R₁ is -halo,preferably —Cl or —F, or wherein R₁ is —C(halo)₃, preferably —CF₃.

(6) The compound of any one of (1) to (5), wherein Q is:

(7) The compound of any one of (1) to (6), wherein n or p is 1 and Q is:

(8) The compound of any one of (1) to (7), wherein J is —OR₂₀ or—N(R₂₀)₂, and preferably is —OR₂₀.

(9) The compound of any one of (1) to (8), wherein each R₂₀ is —H.

(10) The compound of any one of (1) to (9), wherein each Z₃ isindependently selected from —H and —(C₁-C₆)alkyl, and preferably is —H.

(11) The compound of any one of (1) to (10), wherein Z₁ is —H or —OR₇,and preferably is —OR₇, wherein R₇ of the —OR₇ is —H.

(12) The compound of any one of (1) to (11), wherein Z₂ is —H,—(C₁-C₆)alkyl, or —CH₂OR₇, and preferably is —H.

(13) The compound of any one of (1) to (12), wherein Ar₂ is:

(14) The compound of any one of (1) to (12), wherein Ar₂ is:

(15) The compound of any one of (1) to (14), wherein each R₁₄ isindependently -halo, —(C₁-C₆)alkyl, —C(halo)₃, —OR₇, —OC(halo)₃,—S(═O)₂C(halo)₃,

and preferably is —(C₁-C₆)alkyl, —C(halo)₃, —OC(halo)₃, or—S(═O)₂C(halo)₃.

(16) The compound of any one of (1) to (15), wherein each -halo isindependently —Cl or —F.

(17) The compound of any one of (1) to (16), wherein s or q is 1 or 2.

(18) The compound of any one of (1) to (12), wherein Ar₂ is:

(19) The compound of any one of (1) to (12) and (18), wherein R₈ and R₉are each independently selected from —H, -halo, and —(C₁-C₆)alkyl, andpreferably R₈ and R₉ are each independently selected from —H and -halo,wherein preferably each -halo is independently —Cl or —F.

(20) The compound of any one of (1) to (19), wherein at least one Wgroup is N.

(21) The compound of any one of (1) to (20), wherein at least two Wgroups are N.

(22) The compound of any one of (1) to (19), wherein the compounds offormulae I(a)-I(d) are selected from:

(23) The compound of any one of (1) to (22), wherein U is —N(R₂₀)Ar₂ or—OAr₂, and each R₂₀ is preferably —H.

(24) The compound of any one of (1) to (23), wherein each R₃ is —H.

(25) The compound of any one of (1) to (23), wherein at least one R₃ is—(C₁-C₆)alkyl and preferably at least one R₃ is —CH₃ or —CH₂CH₃.

(26) The compound of any one of (1) to (23), wherein at least one R₃ isa group of formula —R₂₃-M-A-R₂₄, wherein:

R₂₃ is a bond, —CH₂— or —(CH₂)₂—;

M is —C(═O)O— or —C(═O)N(R₂₅)—;

A is a bond;

R₂₄ is:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, -(5- to 10-membered)heteroaryl, -(3-        to 7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 substituents independently selected        from -halo, —OH, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)NH₂,        —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₈)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂; or    -   (c) R₂₄ and R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to        10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups;        and

R₂₅ is:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5, or 6 substituents independently        selected from -halo, —OH, —CN, —NH₂, —NO₂, —C(═O)OH, —C(═O)NH₂,        —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂; or    -   (c) R₂₄ and R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to        10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups;

wherein the group designated —R₂₃-M-A-R₂₄ comprises at least one—C(═O)OH group.

(27) The compound of any one of (1) to (23), wherein at least one R₃ isa group of formula —R₂₃-M-A-R₂₄, wherein:

R₂₃ is a bond, —CH₂—, —(CH₂)₂—, or —(CH₂)₃— wherein each carbon of theR₂₃ group is optionally substituted with 1 or 2 substituentsindependently selected from —OH and —(C₁-C₆)alkyl which is optionallysubstituted with 1 or 2 independently selected R₂₂ groups;

the group of formula -M-A-R₂₄ is:

-   -   (a) —H or —C(═O)OH; or    -   (b) —(C₁-C₈)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkoxy,        —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, or -(3- to        7-membered)heterocycle, each of which is optionally substituted        with 1, 2 or 3 independently selected R₂₂ groups; or    -   (c) —P(═O)(OR₂₅)₂ or —OP(═O)(OR₂₅)₂;

each R₂₅ is independently selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, -(5- to 10-membered)heteroaryl, -(3-        to 7-membered)heterocycle, -(7- to        10-membered)bicycloheterocycle, —(C₁-C₆)alkyl-phenyl,        —(C₁-C₆)alkyl-(5- to 10-membered)heteroaryl, —(C₁-C₆)alkyl-(3-        to 7-membered)heterocycle, or —(C₁-C₆)alkyl-(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1 or 2 independently selected R₂₂ groups; and

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, and —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,        -phenyl, and -(3- to 7-membered)heterocycle, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from —OH, -halo, —NH₂, and —C(═O)OH;

wherein preferably the group of formula -M-A-R₂₄ is —C(═O)OH,—P(═O)(OR₂₅)₂, or —OP(═O)(OR₂₅)₂, and at least one R₂₂ is —C(═O)OH.

(28) The compound of any one of (1) to (23), wherein at least one R₃ isselected from —(C₁-C₄)alkyl-C(═O)OH, —C(═O)NH(C₁-C₄)alkyl-C(═O)OH,—CH₂O(C₁-C₄)alkyl-C(═O)OH, —CH₂NH—(C₁-C₄)alkyl-C(═O)OH, —CH₂P(═O)(OH)₂,—CH₂P(═O)(OH)(O(C₁-C₄)alkyl), —CH₂P(═O)(O(C₁-C₄)alkyl)₂,—CH₂OP(═O)(OH)₂, —CH₂OP(═O)(OH)(O(C₁-C₄)alkyl),—CH₂OP(═O)(O(C₁-C₄)alkyl)₂, —CH₂OP(═O)(O-phenyl)₂, —CH₂P(═O)(O-phenyl)₂,

(29) A compound or a pharmaceutically acceptable derivative thereof,selected from:

wherein each W is independently N or C(R₃) and each B is independentlyN(R₃), C(═O), C(═S) or C(R₃)₂, provided that when a W group is N then nosaid nitrogen atom can be connected to 2 or more nitrogen atoms;

U is —N(R₂₀)Ar₂ or —OAr₂;

Ar₁ is:

provided that when Ar₁ is connected to the 7-position of a5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl, then R₂ isnot —CH₂OH;

Ar₂ is:

R₁ is —H, -halo, —(C₁-C₄)alkyl, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —OC(halo)₃, —OCH(halo)₂, or —OCH₂(halo);

R₂ is a group of formula Q, wherein Q is:

Z₁ is —H, —OR₇, —SR₇, —CH₂OR₇, —CH₂SR₇, —CH₂N(R₂₀)₂, or -halo;

Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CH₂OR₇,-phenyl, or -halo;

each Z₃ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, or -phenyl;

J is —OR₂₀, —SR₂₀, —N(R₂₀)₂, or —CN;

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) —C(═NR₂₈)N(R₂₈)₂, —OC(═O)N(R₂₈)₂, —OC(═O)N(R₂₈)S(═O)₂R₂₈,        —O(C₁-C₆)alkyl-N(R₂₈)₂, —O(C₁-C₆)alkyl-OR₂₈,        —S(═O)₂N(R₂₈)C(═O)R₂₈, —S(═O)₂N(R₂₈)C(═O)OR₂₈,        —S(═O)₂N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═O)OR₂₈,        —N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═NR₂₈)N(R₂₈)₂, —N(R₂₈)S(═O)₂R₂₈,        —N(R₂₈)S(═O)₂N(R₂₈)₂,        —N(R₂₈)(C₁-C₆)alkyl-N(R₂₈)₂—N(R₂₈)(C₁-C₆)alkyl-OR₂₈, or        —(C₁-C₆)alkyl-R₂₂; or    -   (c) a group of the formula —R₂₃-M-A-R₂₄;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, —C(═O)—(C₁-C₆)alkyl, or —C(═O)N(R₂₀)₂;

each R₈ and R₉ is independently:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, or -phenyl, each of        which is optionally substituted with 1 or 2-OH groups; or    -   (b) —H, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo),        —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —SC(halo)₃, —SCH(halo)₂,        —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,        —N(R₇)₂, —NR₇OH, —OR₇, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —OC(═O)OR₇, —SR₇, —S(═O)R₇, or —S(═O)₂R₇;

each R₁₁ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —C(═O)R₇, —C(═O)OR₇,—OC(═O)R₇, or —OC(═O)OR₇;

each R₁₄ is independently:

-   -   (a) —H, —CN, —OH, -halo, —N₃, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), -(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl,        —(C₂-C₆)haloalkenyl, —(C₂-C₆)haloalkynyl,        —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)alkoxy-(C₂-C₆)alkenyl,        —(C₁-C₆)alkoxy-(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyl,        —OC(halo)₃, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,        —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂,        —NR₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂,        —N(R₇)C(═O)R₇, —C(═O)R₇, —(C₁-C₆)alkyl-C(═O)OR₇, —C(═O)OR₇,        —OC(═O)R₇, —OC(═O)OR₇, —S(═O)R₇, —S(═O)₂R₇, —S(═O)₂N(R₇)₂,        —S(═O)₂C(halo)₃, —S(═O)₂(3- to 7-membered)heterocycle,        —C(═O)N(R₇)₂, —(C₁-C₆)alkyl-C═NOR₇, —(C₁-C₆)alkyl-C(═O)—N(R₇)₂,        —(C₁-C₆)alkyl-NHS(═O)₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₀ groups;

each R₂₀ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl;

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, and —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,        -phenyl, and -(3- to 7-membered)heterocycle, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from —OH, -halo, —NH₂, and —C(═O)OR₇;

each M is independently a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—OC(═O)—, —C(═O)O—, —O—C(═O)O—, —C(═O)N(R₂₅)—, —N(R₂₅)C(═O)—,—N(R₂₅)S(═O)₂—, —S(═O)₂N(R₂₅)—, —N(R₂₅)—, —OP(═O)(OR₂₅)—,—(R₂₅O)P(═O)(═O)—, —(R₂₅O)P(═O)—, —P(═O)(OR₂₅)—, —OP(═O)₂(OR₂₅)—,—(R₂₅O)P(═O)₂(═O)—, —(R₂₅O)P(═O)₂—, or —P(═O)₂(OR₂₅)—;

each A is independently a bond or —(C₁-C₆)alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R₂₂ groups;

each R₂₃ is independently:

-   -   (a) a bond; or    -   (b) —(C₁-C₆)alkyl-, —(C₂-C₁₀)alkenyl-, or —(C₂-C₁₀)alkynyl-,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, or R₂₃, R₂₄ and        R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to        10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5 or 6 independently selected R₂₂        groups;

R₂₄ and R₂₅ are each independently:

-   -   (a) —H or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, R₂₄ and R₂₅        together, or R₂₃, R₂₄ and R₂₅ together form a        (C₃-C₁₀)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to        7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5 or 6 independently selected R₂₂        groups;

each R₂₈ is independently:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, or -benzyl, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from -halo, —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,        —O(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₄)alkyl, and —N((C₁-C₄)alkyl)₂;

each -halo is independently —F, —Cl, —Br, or —I;

each b is independently selected from the integers 1 and 2;

q is the integer 0, 1, 2, 3 or 4;

r is the integer 0, 1, 2, 3, 4, 5, or 6; and

s is the integer 0, 1, 2, 3, 4, or 5.

(30) The compound of (29), wherein R₂ is in the para-position withrespect to the point of attachment of Ar₁ to the fused rings of II(a),II(b), II(c) or II(d).

(31) The compound of (29) or (30), wherein R₁ is -halo, —(C₁-C₄)alkyl,—C(halo)₃, —CH(halo)₂, or —CH₂(halo) and preferably is -halo, —CH₃, or—C(halo)₃.

(32) The compound of any one of (29) to (31), wherein R₁ is -halo,preferably —Cl or —F, or wherein R₁ is —C(halo)₃, preferably —CF₃.

(33) The compound of any one of (29) to (32), wherein J is —OR₂₀ or—N(R₂₀)₂ and preferably is —OR₂₀.

(34) The compound of any one of (29) to (33), wherein each R₂₀ is —H.

(35) The compound of any one of (29) to (34), wherein each Z₃ isindependently selected from —H and —(C₁-C₆)alkyl, and preferably is —H.

(36) The compound of any one of (29) to (35), wherein Z₁ is —H or —OR₇,and preferably is —OR₇, wherein R₇ of —OR₇ is —H.

(37) The compound of any one of (29) to (36), wherein Z₂ is —H,—(C₁-C₆)alkyl, or —CH₂OR₇, and preferably is —H.

(38) The compound of any one of (29) to (37), wherein Ar₂ is:

(39) The compound of any one of (29) to (37), wherein Ar₂ is:

(40) The compound of any one of (29) to (39), wherein each R₁₄ isindependently -halo, —C(halo)₃, —(C₁-C₆)alkyl, —OR₇, —OC(halo)₃, or—S(═O)₂C(halo)₃, and preferably is —C(halo)₃, —(C₁-C₆)alkyl, —OC(halo)₃or —S(═O)₂C(halo)₃.

(41) The compound of any one of (29) to (40), wherein each -halo isindependently —Cl or —F.

(42) The compound of any one of (29) to (41), wherein s or q is 1 or 2.

(43) The compound of any one of (29) to (37), wherein Ar₂ is:

(44) The compound of any one of (29) to (37) and (43), wherein R₈ and R₉are each independently selected from —H, -halo, and —(C₁-C₆)alkyl, andpreferably R₈ and R₉ are each independently selected from —H and -halo,wherein preferably each -halo is independently —Cl or —F.

(45) The compound of any one of (29) to (44), wherein at least one Wgroup is N.

(46) The compound of any one of (29) to (45), wherein at least two Wgroups are N.

(47) The compound of any one of (29) to (44), wherein the compounds offormulae II(a)-II(d) are selected from:

(48) The compound of any one of (29) to (44), wherein the compound isselected from:

(49) The compound of any one of (29) to (48), wherein each R₃ is —H.

(50) The compound of any one of (29) to (48), wherein at least one R₃ is—(C₁-C₆)alkyl and preferably at least one R₃ is —CH₃ or —CH₂CH₃.

(51) The compound of any one of (29) to (48), wherein at least one R₃ isa group of formula —R₂₃-M-A-R₂₄, wherein:

R₂₃ is a bond, —CH₂— or —(CH₂)₂—;

M is —C(═O)O— or —C(═O)N(R₂₅)—;

A is a bond;

R₂₄ is:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, optionally substituted with 1, 2 or 3        substituents independently selected from -halo, —OH, —NH₂,        —C(═O)OH, —(C₁-C₆)alkoxy, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂; or    -   (c) R₂₄ and R₂₅ together form a (3- to 7-membered)heterocycle        which is optionally substituted with 1, 2, 3, 4, 5, or 6        substituents independently selected from -halo, —OH, —NH₂, —CN,        —NO₂, —C(═O)OH, —C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,        —(C₁-C₆)alkoxycarbonyl, —(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂;

R₂₅ is:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₂-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5, or 6 substituents independently        selected from -halo, —OH, —CN, —NH₂, —NO₂, —C(═O)OH, —C(═O)NH₂,        —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂; or    -   (c) R₂₄ and R₂₅ together form a (3- to 7-membered)heterocycle        which is optionally substituted with 1, 2, 3, 4, 5, or 6        substituents independently selected from -halo, —OH, —NH₂, —CN,        —NO₂, —C(═O)OH, —C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,        —(C₁-C₆)alkoxycarbonyl, —(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and        —N((C₁-C₆)alkyl)₂;

wherein the group designated —R₂₃-M-A-R₂₄ comprises at least one—C(═O)OH group.

(52) The compound of any one of (29) to (48), wherein at least one R₃ isa group of formula —R₂₃-M-A-R₂₄, wherein:

R₂₃ is a bond, —CH₂—, —(CH₂)₂—, or —(CH₂)₃— wherein each carbon of theR₂₃ group is optionally substituted with 1 or 2-CH₃ groups;

the group of formula -M-A-R₂₄ is:

-   -   (a) —C(═O)OH; or    -   (b) —(C₁-C₈)alkoxycarbonyl, —(C₁-C₆)alkoxy, pyrrolidine,        piperidine, piperazine or morpholine, each of which is        substituted with 1, 2 or 3 independently selected R₂₂ groups,        wherein at least one R₂₂ is —C(═O)OH; or    -   (c) —P(═O)(OR₂₅)₂ or —OP(═O)(OR₂₅)₂; and

each R₂₅ is independently selected from:

-   -   (a) —H; or    -   (b) —(C₁-C₆)alkyl, -phenyl, -(3- to 7-membered)heterocycle,        —(C₁-C₆)alkyl-phenyl, or —(C₁-C₆)alkyl-(3- to        7-membered)heterocycle, each of which is optionally substituted        with 1 or 2 independently selected R₂₂ groups;

wherein preferably the group of formula -M-A-R₂₄ is —C(═O)OH,—P(═O)(OR₂₅)₂ or —OP(═O)(OR₂₅)₂, and at least one R₂₂ is —C(═O)OH.

(53) A compound or a pharmaceutically acceptable derivative thereof,selected from:

wherein U is —NH(Ar₂);

Ar₁ is:

Ar₂ is:

R₁ is -halo, —(C₁-C₄)alkyl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) a group of the formula —R₂₃-M-A-R₂₄;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)hydroxyalkyl, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₁-C₆)alkyl-N(R₂₀)₂, —C(═O)—(C₁-C₆)alkyl, or —C(═O)N(R₂₀)₂;

each R₈ and R₉ is independently:

-   -   (a) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, or -phenyl, each of        which is optionally substituted with 1 or 2-OH groups; or    -   (b) —H, —CH₂C(halo)₃, —C(halo)₃, —CH(halo)₂, —CH₂(halo),        —OC(halo)₃, —OCH(halo)₂, —OCH₂(halo), —SC(halo)₃, —SCH(halo)₂,        —SCH₂(halo), —CN, —O—CN, —OH, -halo, —N₃, —NO₂, —CH═NR₇,        —N(R₇)₂, —NR₇OH, —OR₇, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,        —OC(═O)OR₇, —S(═O)R₇, or —S(═O)₂R₇;

each R₁₄ is independently —(C₁-C₆)alkyl, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —(C₁-C₆)haloalkyl, —OC(halo)₃, —OR₇, —S(═O)R₇, —S(═O)₂R₇, or—S(═O)₂C(halo)₃;

each R₂₀ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₈)cycloalkyl;

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, and —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,        -phenyl, and -(3- to 7-membered)heterocycle, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from —OH, -halo, —NH₂, and —C(═O)OR₇;

each M is independently a bond, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—,—OC(═O)—, —C(═O)O—, —O—C(═O)O—, —C(═O)N(R₂₅)—, —N(R₂₅)C(═O)—,—N(R₂₅)S(═O)₂—, —S(═O)₂N(R₂₅)—, —N(R₂₅)—, —OP(═O)(OR₂₅)—,—(R₂₅O)P(═O)(═O)—, —(R₂₅O)P(═O)—, —P(═O)(OR₂₅)—, —OP(═O)₂(OR₂₅)—,—(R₂₅O)P(═O)₂(═O)—, —(R₂₅O)P(═O)₂—, or —P(═O)₂(OR₂₅)—;

each A is independently a bond or —(C₁-C₆)alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R₂₂ groups;

each R₂₃ is independently:

-   -   (a) a bond; or    -   (b) —(C₁-C₆)alkyl-, —(C₂-C₁₀)alkenyl-, or —(C₂-C₁₀)alkynyl-,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, or R₂₃, R₂₄ and        R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5- to        10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5, or 6 independently selected R₂₂        groups;

R₂₄ and R₂₅ are each independently:

-   -   (a) —H or —C(═O)OH; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkyl,        —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,        —(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2 or 3 independently selected R₂₂ groups; or    -   (c) R₂₃ and R₂₄ together, R₂₃ and R₂₅ together, R₂₄ and R₂₅        together, or R₂₃, R₂₄ and R₂₅ together form a        (C₃-C₁₀)cycloalkyl, (5- to 10-membered)heteroaryl, (3- to        7-membered)heterocycle, or (7- to        10-membered)bicycloheterocycle, each of which is optionally        substituted with 1, 2, 3, 4, 5, or 6 independently selected R₂₂        groups;

each -halo is independently —F, —Cl, —Br, or —I;

q is the integer 0, 1, 2, 3 or 4; and

s is the integer 0, 1, 2, 3, 4, or 5.

(54) The compound of (53), wherein the 1,2-dihydroxyethyl substituent ofAr₁ has the (S)-configuration:

(55) The compound of (53), wherein the 1,2-dihydroxyethyl substituent ofAr₁ has the (R)-configuration:

(56) The compound of any one of (53) to (55), wherein R₁ is -halo, —CH₃or —C(halo)₃.

(57) The compound of any one of (53) to (56), wherein R₁ is -halo,preferably —Cl or —F, or wherein R₁ is —C(halo)₃, preferably —CF₃.

F.

(58) The compound of any one of (53) to (57), wherein each -halo isindependently —Cl or —F.

(59) The compound of any one of (53) to (58), wherein s or q is 1 or 2.

(60) The compound of any one of (53) to (59), wherein Ar₂ is:

wherein R₈ and R₉ are each independently selected from —H, —CH₃,iso-propyl, tert-butyl, —OCH₃, —OCH₂CH₃, —S(═O)₂C(halo)₃, -halo,—C(halo)₃, and —OC(halo)₃, wherein preferably each -halo isindependently —Cl, —Br or —F, —C(halo)₃ is preferably —CF₃, and—OC(halo)₃ is preferably —OCF₃.

(61) The compound of any one of (53) to (60), wherein Ar₂ is:

wherein R₈ and R₉ are each independently selected from —H, —CH₃,iso-propyl, tert-butyl, —OCH₃, —OCH₂CH₃, —S(═O)₂C(halo)₃, -halo,—C(halo)₃, and —OC(halo)₃, wherein preferably each -halo isindependently —Cl, —Br or —F, —C(halo)₃ is preferably —CF₃, and—OC(halo)₃ is preferably —OCF₃.

(62) The compound of any one of (53) to (59), wherein Ar₂ is:

wherein R₁₄ is —OCF₃, —CF₃, —S(═O)₂CF₃, or —C(CH₃)₃.

(63) The compound of any one of (53) to (59), wherein Ar₂ is:

(64) The compound of any one of (53) to (63), wherein the compound isselected from:

(65) The compound of any one of (53) to (64), wherein each R₃ is —H.

(66) The compound of any one of (53) to (64), wherein at least one R₃ is—(C₁-C₆)alkyl and preferably at least one R₃ is —CH₃ or —CH₂CH₃.

(67) The compound of any one of (53) to (64), wherein at least one R₃is:

(68) The compound of any one of (53) to (65), wherein the compound is:

(69) The compound of any one of (53) to (65), wherein the compound is:

(70) The compound of any one of (53) to (65), wherein the compound is:

(71) The compound of any one of (53) to (65), wherein the compound is:

(72) The compound of any one of (53) to (65), wherein the compound is:

(73) The compound of any one of (53) to (65), wherein the compound is:

(74) The compound of any one of (53) to (65), wherein the compound is:

(75) The compound of any one of (1) to (74), wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt.

(76) A composition comprising a compound of any one of (1) to (75) or apharmaceutically acceptable derivative of the compound of any one of (1)to (74) and a pharmaceutically acceptable carrier or excipient.

(77) A method for treating or preventing pain, UI, an ulcer, IBD, or IBSin an animal, comprising administering to an animal in need thereof, aneffective amount of a compound of any one of (1) to (75) or apharmaceutically acceptable derivative of the compound of any one of (1)to (74).

(78) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof a compound of any one of (1) to (75) or a pharmaceutically acceptablederivative of the compound of any one of (1) to (74).

(79) A use of a compound of any one of (1) to (75) or a pharmaceuticallyacceptable derivative of the compound of any one of (1) to (74) in theproduction of a medicament for the treatment or prevention of pain, UI,an ulcer, IBD, or IBS in an animal.

(80) The compound of any one of (1) to (75) for use as a medicament.

4.1. COMPOUNDS OF FORMULAE I

The invention encompasses compounds of formula I(a):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae I(a), I(b), I(c) andI(d).

The invention also encompasses compounds of formula I(b):

or a pharmaceutically acceptable derivative thereof, where W, B, Ar₁,and U are as defined above for compounds of formulae I(a), I(b), I(c)and I(d).

The invention also encompasses compounds of formula I(c):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae I(a), I(b), I(c) andI(d).

The invention also encompasses compounds of the formula I(c)′:

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae I(a), I(b), I(c) andI(d).

The invention also encompasses compounds of formula I(d):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formula I(a), I(b), I(c) and I(d).

Certain embodiments of formulae I(a), I(b), I(c) and I(d) are presentedbelow.

In one embodiment, a compound of formula I(a), I(b), I(c) or I(d) is apharmaceutically acceptable derivative of a compound of formula I(a),I(b), I(c) or I(d).

In another embodiment, a compound of formula I(a), I(b), I(c) or I(d) isa compound of formula I(a), I(b), I(c) or I(d) where the derivative is apharmaceutically acceptable salt.

In another embodiment, a compound of formula I(a), I(b), I(c) or I(d) isa pharmaceutically acceptable salt of a compound of formula I(a), I(b),I(c) or I(d).

In another embodiment, at least one W group is N.

In another embodiment, at least two W groups are N.

In another embodiment, a compound of formula I(a) is a compound offormula I(aa):

In another embodiment, a compound of formula I(a) is a compound offormula I(ab):

In another embodiment, a compound of formula I(a) is a compound offormula I(ac):

In another embodiment, a compound of formula I(a) is a compound offormula I(ad):

In another embodiment, a compound of formula I(a) is a compound offormula I(ae):

In another embodiment, a compound of formula I(a) is a compound offormula I(af):

In another embodiment, a compound of formula I(a) is a compound offormula I(ag):

In another embodiment, a compound of formula I(a) is a compound offormula I(ah):

In another embodiment, a compound of formula I(b) is a compound offormula I(ba):

In another embodiment, a compound of formula I(b) is a compound offormula I(bb):

In another embodiment, a compound of formula I(b) is a compound offormula I(bc):

In another embodiment, a compound of formula I(b) is a compound offormula I(bd):

In another embodiment, a compound of formula I(b) is a compound offormula I(be):

In another embodiment, a compound of formula I(b) is a compound offormula I(bf):

In another embodiment, a compound of formula I(b) is a compound offormula I(bg):

In another embodiment, a compound of formula I(b) is a compound offormula I(bh):

In another embodiment, when the Ar₁ group of a compound of formula I(b)is connected to a 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁is —Cl, then R₂ is not —CH₂OH.

In another embodiment, when the Ar₁ group of a compound of formula I(b)is connected to a tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl,then R₂ is not —CH₂OH.

In another embodiment, a compound of formula I(c) is a compound offormula I(ca):

In another embodiment, a compound of formula I(c) is a compound offormula I(cb):

In another embodiment, a compound of formula I(c) is a compound offormula I(cc):

In another embodiment, a compound of formula I(c) is a compound offormula I(cd):

In another embodiment, a compound of formula I(c) is a compound offormula I(ce):

In another embodiment, a compound of formula I(c) is a compound offormula I(cf):

In another embodiment, a compound of formula I(c) is a compound offormula I(cg):

In another embodiment, a compound of formula I(c) is a compound offormula I(ch):

In another embodiment, a compound of formula I(d) is a compound offormula I(da):

In another embodiment, a compound of formula I(d) is a compound offormula I(db):

In another embodiment, a compound of formula I(d) is a compound offormula I(dc):

In another embodiment, a compound of formula I(d) is a compound offormula I(dd):

In another embodiment, a compound of formula I(d) is a compound offormula I(de):

In another embodiment, a compound of formula I(d) is a compound offormula I(df):

In another embodiment, a compound of formula I(d) is a compound offormula I(dg):

In another embodiment, a compound of formula I(d) is a compound offormula I(dh):

In another embodiment, a compound of formula I(d) is a compound offormula I(di):

In another embodiment, n or p is 1.

In another embodiment, n or p is 2.

In another embodiment, n is 3.

In another embodiment, Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is:

In another embodiment, Ar₁ is:

In another embodiment, Ar₁ is:

In another embodiment, Ar₁ is:

In another embodiment, Ar₁ is:

In another embodiment, Ar₁ is:

In another embodiment, n or p is 1 and R₂ is in the para-position withrespect to the point of attachment of Ar₁ to the fused rings of I(a),I(b), I(c) or I(d).

In another embodiment, U is —OAr₂.

In another embodiment, U is —N(R₂₀)Ar₂.

In another embodiment, U is —SAr₂.

In another embodiment, U is —S(═O)Ar₂.

In another embodiment, U is —S(═O)₂Ar₂.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

s is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

s is 2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

q is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, at least one R₁₄ is -halo.

In another embodiment, at least one R₁₄ is —C(halo)₃.

In another embodiment, at least one R₁₄ is —(C₁-C₆)alkyl.

In another embodiment, at least one R₁₄ is —OR₇.

In another embodiment, at least one R₁₄ is —OC(halo)₃.

In another embodiment, at least one R₁₄ is —S(═O)₂C(halo)₃.

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₃ is —CH₃.

In another embodiment, at least one R₃ is —CH₂CH₃.

In another embodiment, at least one R₃ is —(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —C(═O)NH(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂O(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂NH—(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)(O(C₁-C₄)alkyl).

In another embodiment, at least one R₃ is —CH₂P(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)(O(C₁-C₄)alkyl).

In another embodiment, at least one R₃ is —CH₂OP(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is independently or—(C₁-C₆)alkyl.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where said group is substituted with at least one R₂₂ andeach R₂₂ is independently selected from —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl,—(C₁-C₆)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,-phenyl, and -(3- to 7-membered)heterocycle, each of which is optionallysubstituted with 1, 2 or 3 substituents independently selected from —OH,-halo, —NH₂, and —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where said group is substituted with at least one R₂₂ andwhere each R₂₂ is independently selected from -halo, —OH, —NH₂, —CN,—NO₂, and —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where said group is substituted with at least one R₂₂ andwhere R₂₂ is —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₃ is a bond, —CH₂—, —(CH₂)₂—, or —(CH₂)₃— whereeach carbon of the R₂₃ group is optionally substituted with 1 or 2substituents independently selected from —OH and —(C₁-C₆)alkyl which isoptionally substituted with 1 or 2 independently selected R₂₂ groups.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₃ is a bond, —CH₂— or —(CH₂)₂—.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where M is —C(═O)O— or —C(═O)N(R₂₅)—.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where A is a bond.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ is —H.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ is —(C₁-C₆)alkyl, -phenyl, -(5- to10-membered)heteroaryl, -(3- to 7-membered)heterocycle, or -(7- to10-membered)bicycloheterocycle, each of which is optionally substitutedwith 1, 2 or 3 substituents independently selected from -halo, —OH,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—(C₁-C₈)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and —N((C₁-C₆)alkyl)₂.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where M is —C(═O)N(R₂₅) and R₂₅ is —H.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₅ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from -halo, —OH, —CN, —NH₂, —NO₂, —C(═O)OH,—C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₆)alkoxycarbonyl,—(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—NH(C₁-C₆)alkyl, and —N((C₁-C₆)alkyl)₂.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ and R₂₅ together form a (C₃-C₁₀)cycloalkyl, (5-to 10-membered)heteroaryl, (3- to 7-membered)heterocycle, or (7- to10-membered)bicycloheterocycle, each of which is optionally substitutedwith 1, 2 or 3 independently selected R₂₂ groups.

In another embodiment, the group designated —R₂₃-M-A-R₂₄ comprises atleast one-C(═O)OH group.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —C(═O)OH or —H.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is—(C₁-C₈)alkoxycarbonyl, —(C₁-C₈)alkanoyloxy, —(C₁-C₆)alkoxy,—NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, or -(3- to 7-membered)heterocycle,each of which is optionally substituted with 1, 2 or 3 independentlyselected R₂₂ groups.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —P(═O)(OR₂₅)₂ or—OP(═O)(OR₂₅)₂, where each R₂₅ is independently —H or selected from—(C₁-C₆)alkyl, -phenyl, -(5- to 10-membered)heteroaryl, -(3- to7-membered)heterocycle, -(7- to 10-membered)bicycloheterocycle,—(C₁-C₆)alkyl-phenyl, —(C₁-C₆)alkyl-(5- to 10-membered)heteroaryl,—(C₁-C₆)alkyl-(3- to 7-membered)heterocycle, and —(C₁-C₆)alkyl-(7- to10-membered)bicycloheterocycle, each of which is optionally substitutedwith 1 or 2 independently selected R₂₂ groups.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —C(═O)OH,—P(═O)(OR₂₅)₂ or —OP(═O)(OR₂₅)₂.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, and which bridge optionally contains —HC═CH— withinthe (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₆)bridge,which is unsubstituted or substituted with an R₈ group, and which bridgeoptionally contains —HC═CH— within the (C₂-C₆)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with 1, 2 or 3 independentlyselected R₈ groups, which bridge optionally contains —HC═CH— within the(C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted or substituted with an R₈ group, which bridgeoptionally contains —HC═CH— within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂-C₃)bridge,which is unsubstituted and which bridge optionally contains —HC═CH—within the (C₂-C₃)bridge.

In another embodiment, two R₃ groups together form a (C₂)bridge, a—HC═CH— bridge, or a (C₃)bridge each of which is unsubstituted.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —(C₁-C₄)alkyl.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, J is —OR₂₀, —SR₂₀ or —N(R₂₀)₂.

In another embodiment, J is —OR₂₀.

In another embodiment, J is —OH.

In another embodiment, J is —CN.

In another embodiment, Z₁ is —H.

In another embodiment, Z₁ is —OH.

In another embodiment, Z₁ is —OCH₃.

In another embodiment, Z₁ is —CH₂OH.

In another embodiment, Z₂ is —CH₂OR₇.

In another embodiment, Z₂ is —CH₂OH.

In another embodiment, Z₂ is —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -phenyl, or -halo.

In another embodiment, Z₂ is —H.

In another embodiment, Z₂ is —CH₃.

In another embodiment, Z₃ is —H.

In another embodiment, Z₃ is —CH₃.

In another embodiment, Z₄ is —H.

In another embodiment, Z₄ is —(C₁-C₆)alkyl.

In another embodiment, Z₄ is —N(R₂₀)₂.

In another embodiment Z₄ is —OR₂₀.

In another embodiment, Z₄ is —OH.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is independently —H or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is independently —(C₁-C₆)alkyl or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —CH₃.

In another embodiment, each R₂₀ is —(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is cyclohexyl.

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

where the compound of formulae I(a), I(b), I(c) or I(d) is racemic.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 60%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 70%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 80%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 90%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 99%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 60%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 70%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 80%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 90%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 99%.

Aqueous solubility of compounds is often a desirable feature. Forexample, aqueous solubility of a compound permits that compound to bemore easily formulated into a variety of dosage forms that can beadministered to an animal. When a compound is not fully soluble in theblood, it can precipitate in the blood, and the animal's exposure to thedrug will accordingly not correspond to the administered dose. Aqueoussolubility increases the likelihood that a compound will not precipitatein an animal's blood, and increases the ability to predict exposure atthe target sight of the compound. Compounds of formula I(a), I(b), I(c)or I(d) are believed to be highly soluble in aqueous solution.

4.2. COMPOUNDS OF FORMULAE II

Preferred compounds of formulae I(a), I(b), I(c) and I(d) are compoundsof formulae II(a), II(c) and II(d):

or a pharmaceutically acceptable derivative thereof, where:

each W is independently N or C(R₃) and each B is independently N(R₃),C(═O), C(═S) or C(R₃)₂, provided that when a W group is N then no saidnitrogen atom can be connected to 2 or more nitrogen atoms;

U is —N(R₂₀)Ar₂ or —OAr₂;

Ar₁ is:

provided that when Ar₁ is connected to the 7-position of a5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl, then R₂ isnot —CH₂OH;

Ar₂ is:

R₂ is a group of formula Q, where Q is:

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) —C(═NR₂₈)N(R₂₈)₂, —OC(═O)N(R₂₈)₂, —OC(═O)N(R₂₈)S(═O)₂R₂₈,        —O(C₁-C₆)alkyl-N(R₂₈)₂, —O(C₁-C₆)alkyl-OR₂₈,        —S(═O)₂N(R₂₈)C(═O)R₂₈, —S(═O)₂N(R₂₈)C(═O)OR₂₈,        —S(═O)₂N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═O)OR₂₈,        —N(R₂₈)C(═O)N(R₂₈)₂, —N(R₂₈)C(═NR₂₈)N(R₂₈)₂, —N(R₂₈)S(═O)₂R₂₈,        —N(R₂₈)S(═O)₂N(R₂₈)₂, —N(R₂₈)(C₁-C₆)alkyl-N(R₂₈)₂,        —N(R₂₈)(C₁-C₆)alkyl-OR₂₈, or —(C₁-C₆)alkyl-R₂₂; or    -   (c) a group of the formula —R₂₃-M-A-R₂₄;

each R₁₄ is independently:

-   -   (a) —H, —CN, —OH, -halo, —N₃, or —NO₂; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, -phenyl, —C(halo)₃, —CH(halo)₂,        —CH₂(halo), -(3- to 7-membered)heterocycle, —(C₁-C₆)haloalkyl,        —(C₂-C₆)haloalkenyl, —(C₂-C₆)haloalkynyl,        —(C₂-C₆)hydroxyalkenyl, —(C₂-C₆)hydroxyalkynyl,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —(C₁-C₆)alkoxy-(C₂-C₆)alkenyl,        —(C₁-C₆)alkoxy-(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyl,        —OC(halo)₃, —CH═NR₇, —N(R₇)₂, —NR₇OH, —OR₇, —SR₇,        —O(CH₂)_(b)OR₇, —O(CH₂)_(b)SR₇, —O(CH₂)_(b)N(R₇)₂,        —N(R₇)(CH₂)_(b)OR₇, —N(R₇)(CH₂)_(b)SR₇, —N(R₇)(CH₂)_(b)N(R₇)₂,        —N(R₇)C(═O)R₇, —C(═O)R₇, —(C₁-C₆)alkyl-C(═O)OR₇, —C(═O)OR₇,        —OC(═O)R₇, —OC(═O)OR₇, —S(═O)R₇, —S(═O)₂R₇, —S(═O)₂N(R₇)₂,        —S(═O)₂C(halo)₃, —S(═O)₂(3- to 7-membered)heterocycle,        —C(═O)N(R₇)₂, —(C₁-C₆)alkyl-C═NOR₇, —(C₁-C₆)alkyl-C(═O)—N(R₇)₂,        —(C₁-C₆)alkyl-NHS(═O)₂N(R₇)₂, or —(C₁-C₆)alkyl-C(═NH)—N(R₇)₂,        each of which is optionally substituted with 1, 2 or 3        independently selected R₂₀ groups;

each R₂₂ is independently selected from:

-   -   (a) —H, —OH, -halo, —NH₂, —CN, —NO₂, and —C(═O)OR₇; or    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₁-C₆)alkanoyl, —(C₁-C₆)alkoxycarbonyl,        —(C₁-C₈)alkanoyloxy, —(C₁-C₈)alkylthio,        —(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂,        -phenyl, and -(3- to 7-membered)heterocycle, each of which is        optionally substituted with 1, 2 or 3 substituents independently        selected from —OH, -halo, —NH₂, and —C(═O)OH; and

the other moieties are as defined for compounds of formulae I(a)-I(d).

Compounds of formulae II(a), II(c) and II(d) are believed to be highlysoluble in aqueous solutions at either pH 6.8 or pH 1.2 and are believedto be very potent at the TRPV1 receptor.

Certain embodiments of formulae II(a), II(b), II(c) and II(d) arepresented below.

In one embodiment, a compound of formula II(a), II(b), II(c) or II(d) isa pharmaceutically acceptable derivative of a compound of formulaeII(a), II(c) or II(d).

In another embodiment, a compound of formula II(a), II(b), II(c) orII(d) is a compound of formulae II(a), II(c) or II(d) where thederivative is a pharmaceutically acceptable salt.

In another embodiment, a compound of formula II(a), II(b), II(c) orII(d) is a pharmaceutically acceptable salt of a compound of formulaeII(a), II(b), II(c) or II(d).

In another embodiment, the invention encompasses compounds of formulaII(a):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae II(a), II(b), II(c) andII(d).

In another embodiment, the invention encompasses compounds of formulaII(b):

or a pharmaceutically acceptable derivative thereof, where W, B, Ar₁,and U are as defined above for compounds of formulae II(a), II(b), II(c)and II(d).

In another embodiment, the invention encompasses compounds of formulaII(c):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae II(a), II(b), II(c) andII(d).

In another embodiment, the invention encompasses compounds of formulaII(c)′:

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae II(a), II(b), II(c) andII(d).

In another embodiment, the invention encompasses compounds of formulaII(d):

or a pharmaceutically acceptable derivative thereof, where W, Ar₁, and Uare as defined above for compounds of formulae II(a), II(b), II(c) andII(d).

In another embodiment, at least one W group is N.

In another embodiment, at least two W groups are N.

In another embodiment, a compound of formula II(a) is a compound offormula II(aa):

In another embodiment, a compound of formula II(a) is a compound offormula II(ab):

In another embodiment, a compound of formula II(a) is a compound offormula II(ac):

In another embodiment, a compound of formula II(a) is a compound offormula II(ad):

In another embodiment, a compound of formula II(a) is a compound offormula II(ae):

In another embodiment, a compound of formula II(a) is a compound offormula II(af):

In another embodiment, a compound of formula II(a) is a compound offormula II(ag):

In another embodiment, a compound of formula II(a) is a compound offormula II(ah):

In another embodiment, a compound of formula II(b) is a compound offormula II(ba):

In another embodiment, when the Ar₁ group of a compound of formula II(b)is connected to a 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring and R₁is —Cl, then R₂ is not —CH₂OH.

In another embodiment, when the Ar₁ group of a compound of formula II(b)is connected to a tetrahydropyrido[3,4-d]pyrimidine ring and R₁ is —Cl,then R₂ is not —CH₂OH.

In another embodiment, a compound of formula II(c) is a compound offormula II(ca):

In another embodiment, a compound of formula II(c) is a compound offormula II(cb):

In another embodiment, a compound of formula II(d) is a compound offormula II(da):

In another embodiment, Ar₁ is a pyridyl group.

In another embodiment, Ar₁ is a pyrimidinyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, R₂ is in the para-position with respect to thepoint of attachment of Ar₁ to the fused rings of II(a), II(b), II(c) orII(d).

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(a) is:

In another embodiment, a compound of formula II(b) is:

In another embodiment, a compound of formula II(c) is:

In another embodiment, a compound of formula II(c) is:

In another embodiment, a compound of formula II(d) is:

In another embodiment, U is —OAr₂.

In another embodiment, U is —N(R₂₀)Ar₂.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

s is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

s is 2, and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

q is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, at least one R₁₄ is -halo.

In another embodiment, at least one R₁₄ is —C(halo)₃.

In another embodiment, at least one R₁₄ is —(C₁-C₆)alkyl.

In another embodiment, at least one R₁₄ is —OR₇.

In another embodiment, at least one R₁₄ is —OC(halo)₃.

In another embodiment, at least one R₁₄ is —S(═O)₂C(halo)₃.

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₃ is —CH₃.

In another embodiment, at least one R₃ is —CH₂CH₃.

In another embodiment, at least one R₃ is —(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —C(═O)NH(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂O(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂NH—(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)(O(C₁-C₄)alkyl.

In another embodiment, at least one R₃ is —CH₂P(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)(O(C₁-C₄)alkyl).

In another embodiment, at least one R₃ is —CH₂OP(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is independently —H, or—(C₁-C₆)alkyl.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where said group is substituted with at least one R₂₂ andR₂₂ is —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₃ is a bond, —CH₂—, —(CH₂)₂— or —(CH₂)₃— and eachcarbon atom is optionally substituted with 1 or 2-CH₃ groups.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₃ is a bond, —CH₂— or —(CH₂)₂—.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ is —(C₁-C₆)alkyl, optionally substituted with 1,2 or 3 substituents independently selected from -halo, —OH, —NH₂,—C(═O)OH, —(C₁-C₆)alkoxy, —NH(C₁-C₆)alkyl, and —N((C₁-C₆)alkyl)₂.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ is —H.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₅ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₂-C₈)alkanone, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—(C₃-C₁₀)cycloalkyl, -(5- to 10-membered)heteroaryl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from -halo, —OH, —CN, —NH₂, —NO₂, —C(═O)OH,—C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —(C₁-C₆)alkoxycarbonyl,—(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio, —(C₁-C₆)alkoxy-(C₁-C₆)alkyl,—NH(C₁-C₆)alkyl, and —N((C₁-C₆)alkyl)₂.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₅ is —H.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where R₂₄ and R₂₅ together form a (3- to7-membered)heterocycle which is optionally substituted with 1, 2, 3, 4,5, or 6 substituents independently selected from -halo, —OH, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)NH₂, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—(C₁-C₆)alkoxycarbonyl, —(C₁-C₆)alkanoyloxy, —(C₁-C₈)alkylthio,—(C₁-C₆)alkoxy-(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, and —N((C₁-C₆)alkyl)₂.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where M is —C(═O)O— or —C(═O)N(R₂₅)—.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where A is a bond.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group designated —R₂₃-M-A-R₂₄ comprises at leastone —C(═O)OH group.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is—(C₁-C₈)alkoxycarbonyl, —(C₁-C₆)alkoxy, pyrrolidine, piperidine,piperazine or morpholine, each of which is substituted with 1, 2 or 3independently selected R₂₂ groups, where at least one R₂₂ is —C(═O)OH.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —P(═O)(OR₂₅)₂ or—OP(═O)(OR₂₅)₂, where each R₂₅ is independently —H or selected from—(C₁-C₆)alkyl, -phenyl, -(3- to 7-membered)heterocycle,—(C₁-C₆)alkyl-phenyl, and —(C₁-C₆)alkyl-(3- to 7-membered)heterocycle,each of which is optionally substituted with 1 or 2 independentlyselected R₂₂ groups.

In another embodiment, at least one R₃ is a group of formula—R₂₃-M-A-R₂₄, where the group of formula -M-A-R₂₄ is —C(═O)OH,—P(═O)(OR₂₅)₂ or —OP(═O)(OR₂₅)₂.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —(C₁-C₄)alkyl.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, J is —OR₂₀, —SR₂₀ or —N(R₂₀)₂.

In another embodiment, J is —OR₂₀.

In another embodiment, J is —OH.

In another embodiment, J is —CN.

In another embodiment, Z₁ is —H.

In another embodiment, Z₁ is —OR₇.

In another embodiment, Z₁ is —OH.

In another embodiment, Z₁ is —OCH₃.

In another embodiment, Z₁ is —CH₂OH.

In another embodiment, Z₂ is —CH₂OR₇.

In another embodiment, Z₂ is —CH₂OH.

In another embodiment, Z₂ is —H, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,-phenyl, or -halo.

In another embodiment, Z₂ is —H.

In another embodiment, Z₂ is —CH₃.

In another embodiment, Z₃ is —H.

In another embodiment, Z₃ is —CH₃.

In another embodiment, Z₃ is —(C₁-C₆)alkyl.

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

In another embodiment, Q is:

where the compound of formulae II(a), II(b), II(c) or II(d) is racemic.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 60%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 70%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 80%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 90%.

In another embodiment, Q is:

where the % ee of the R enantiomer is greater than 99%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 60%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 70%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 80%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 90%.

In another embodiment, Q is:

where the % ee of the S enantiomer is greater than 99%.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is independently —H or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is independently —(C₁-C₆)alkyl or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —CH₃.

In another embodiment, each R₂₀ is —(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is cyclohexyl.

4.3. COMPOUNDS OF FORMULAE III

Preferred compounds of formulae II(a), II(b), II(c) and II(d) arecompounds of formulae III(a), III(b), III(c), III(d), III(f), III(g),III(h), III(i), III(j), III(k) and III(l):

or a pharmaceutically acceptable derivative thereof, where:

U is —NH(Ar₂);

Ar₁ is:

Ar₂ is:

R₁ is -halo, —(C₁-C₄)alkyl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₃ is independently:

-   -   (a) —H, -halo, —CH₂OR₇, —CN, —NO₂, or —NH₂; or    -   (b) a group of the formula —R₂₃-M-A-R₂₄; and

each R₁₄ is independently —(C₁-C₆)alkyl, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —(C₁-C₆)haloalkyl, —OC(halo)₃, —OR₇, —S(═O)R₇, —S(═O)₂R₇, or—S(═O)₂C(halo)₃; and

the other moieties are as defined for compounds of formulae II(a)-II(d).

Compounds of formulae III(a), III(b), III(c), III(d), III(e), III(f),III(g), III(h), III(i), III(j), III(k) and III(l) are believed to behighly soluble in aqueous solutions at either pH 6.8 or pH 1.2 and arebelieved to be very potent at the TRPV1 receptor.

Certain embodiments of formulae III(a), III(b), III(c), III(d), III(e),III(f), III(g), III(h), III(i), III(j), III(k) and III(l) are presentedbelow.

In one embodiment, a compound of formula III(a), III(b), III(c), III(d),III(e), III(f), III(g), III(h), III(i), III(j), III(k) or III(l) is apharmaceutically acceptable derivative of a compound of formula III(a),III(b), III(c), III(d), III(e), III(f), III(g), III(h), III(i), III(j),III(k) or III(l).

In another embodiment, a compound of formula III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) or III(l)is a compound of formula III(a), III(b), III(c), III(d), III(e), III(f),III(g), III(h), III(i), III(j), III(k) or III(l) where the derivative isa pharmaceutically acceptable salt.

In another embodiment, a compound of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) or III(l)is a pharmaceutically acceptable salt of a compound of formulae III(a),III(b), III(c), III(e), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, the invention encompasses compounds of formulaIII(a):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(b):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(c):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, the invention encompasses compounds of formulaIII(d):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(g), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(e):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, the invention encompasses compounds of formulaIII(f):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, the invention encompasses compounds of formulaIII(g):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, the invention encompasses compounds of formulaIII(h):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(g), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(i):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(e), III(g), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(j):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(d),III(e), III(g), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(k):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(h), III(i), III(j), III(k) or III(l).

In another embodiment, the invention encompasses compounds of formulaIII(g):

or a pharmaceutically acceptable derivative thereof, where R₃, Ar₁, andU are as defined above for compounds of formulae III(a), III(b), III(c),III(d), III(e), III(f), III(g), III(h), III(i), III(j), III(k) orIII(l).

In another embodiment, a compound of formula III(a) is:

In another embodiment, a compound of formula III(b) is:

In another embodiment, a compound of formula III(c) is:

In another embodiment, a compound of formula III(d) is:

In another embodiment, a compound of formula III(e) is:

In another embodiment, a compound of formula III(f) is:

In another embodiment, a compound of formula III(g) is:

In another embodiment, a compound of formula III(h) is:

In another embodiment, a compound of formula III(i) is:

In another embodiment, a compound of formula III(j) is:

In another embodiment, a compound of formula III(k) is:

In another embodiment, a compound of formula III(l) is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

In another embodiment, Ar₂ is:

s is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —OR₇,—N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

s is 2 and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

where R₁₄ is —OCF₃, —CF₃, —S(═O)₂CF₃, or —C(CH₃)₃.

In another embodiment, Ar₂ is:

where each R₁₄ is independently —OCF₃, —CF₃, —S(═O)₂CF₃, or —C(CH₃)₃.

In another embodiment, Ar₂ is:

q is 1 and R₁₄ is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —OC(halo)₃, —N(R₇)₂,—S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

q is 2 and each R₁₄ is independently —(C₁-C₆)alkyl, -halo, —C(halo)₃,—OC(halo)₃, —OR₇, —N(R₇)₂, —S(═O)₂R₇, or —S(═O)₂C(halo)₃.

In another embodiment, Ar₂ is:

where R₁₄ is —OCF₃, —CF₃, —S(═O)₂CF₃, or —C(CH₃)₃.

In another embodiment, Ar₂ is:

where each R₁₄ is independently —OCF₃, —CF₃, —S(═O)₂CF₃, or —C(CH₃)₃.

In another embodiment, Ar₂ is:

In another embodiment, at least one R₁₄ is -halo.

In another embodiment, at least one R₁₄ is —C(halo)₃.

In another embodiment, at least one R₁₄ is —(C₁-C₆)alkyl.

In another embodiment, at least one R₁₄ is —OR₇.

In another embodiment, at least one R₁₄ is —OC(halo)₃.

In another embodiment, at least one R₁₄ is —S(═O)₂C(halo)₃.

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₁₄ is:

In another embodiment, at least one R₃ is —CH₃.

In another embodiment, at least one R₃ is —CH₂CH₃.

In another embodiment, at least one R₃ is —(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —C(═O)NH(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂O(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂NH—(C₁-C₄)alkyl-C(═O)OH.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(OH)(O(C₁-C₄)alkyl.

In another embodiment, at least one R₃ is —CH₂OP(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(OH)(O(C₁-C₄)alkyl).

In another embodiment, at least one R₃ is —CH₂OP(═O)(O(C₁-C₄)alkyl)₂.

In another embodiment, at least one R₃ is —CH₂OP(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is —CH₂P(═O)(O-phenyl)₂.

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is:

In another embodiment, at least one R₃ is independently —H, or—(C₁-C₆)alkyl.

In another embodiment, s or q is 0.

In another embodiment, s or q is 1.

In another embodiment, s or q is 2.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —(C₁-C₄)alkyl.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, the 1,2-dihydroxyethyl substituent of Ar₁ has the(S)-configuration:

In another embodiment, the 1,2-dihydroxyethyl substituent of Ar₁ has the(R)-configuration:

In another embodiment Q is:

where the compound of formulae III(a), III(b), III(c) or III(d) isracemic.

In another embodiment Q is:

where the % ee of the R enantiomer is greater than 60%.

In another embodiment Q is:

where the % ee of the R enantiomer is greater than 70%.

In another embodiment Q is:

where the % ee of the R enantiomer is greater than 80%.

In another embodiment Q is:

where the % ee of the R enantiomer is greater than 90%.

In another embodiment Q is:

where the % ee of the R enantiomer is greater than 99%.

In another embodiment Q is:

where the % ee of the S enantiomer is greater than 60%.

In another embodiment Q is:

where the % ee of the S enantiomer is greater than 70%.

In another embodiment Q is:

where the % ee of the S enantiomer is greater than 80%.

In another embodiment Q is:

where the % ee of the S enantiomer is greater than 90%.

In another embodiment Q is:

where the % ee of the S enantiomer is greater than 99%.

In another embodiment, each R₂₀ is independently —H or —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is independently —H or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is independently —(C₁-C₆)alkyl or—(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is —H.

In another embodiment, each R₂₀ is —(C₁-C₆)alkyl.

In another embodiment, each R₂₀ is —CH₃.

In another embodiment, each R₂₀ is —(C₃-C₈)cycloalkyl.

In another embodiment, each R₂₀ is cyclohexyl.

As an illustration, some compounds of formulae I-III are provided inTables 1-44.

TABLE 1 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U AAA (a or b) —Cl

AAB (a or b) —F

AAC (a or b) —CF₃

AAD (a or b) —CH₃

AAE (a or b) —Cl

AAF (a or b) —F

AAG (a or b) —CF₃

AAH (a or b) —CH₃

AAI (a or b) —Cl

AAJ (a or b) —F

AAK (a or b) —CF₃

AAL (a or b) —CH₃

AAM (a or b) —Cl

AAN (a or b) —F

AAO (a or b) —CF₃

AAP (a or b) —CH₃

AAQ (a or b) —Cl

AAR (a or b) —F

AAS (a or b) —CF₃

AAT (a or b) —CH₃

AAU (a or b) —Cl

AAV (a or b) —F

AAW (a or b) —CF₃

AAX (a or b) —CH₃

AAY (a or b) —Cl

AAZ (a or b) —F

ABA (a or b) —CF₃

ABB (a or b) —CH₃

TABLE 2 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ABC (a or b) —Cl

ABD (a or b) —F

ABE (a or b) —CF₃

ABF (a or b) —CH₃

ABG (a or b) —Cl

ABH (a or b) —F

ABI (a or b) —CF₃

ABJ (a or b) —CH₃

ABK (a or b) —Cl

ABL (a or b) —F

ABM (a or b) —CF₃

ABN (a or b) —CH₃

ABO (a or b) —Cl

ABP (a or b) —F

ABQ (a or b) —CF₃

ABR (a or b) —CH₃

ABS (a or b) —Cl

ABT (a or b) —F

ABU (a or b) —CF₃

ABV (a or b) —CH₃

ABW (a or b) —Cl

ABX (a or b) —F

ABY (a or b) —CF₃

ABZ (a or b) —CH₃

ACA (a or b) —Cl

ACB (a or b) —F

ACC (a or b) —CF₃

ACD (a or b) —CH₃

TABLE 3 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ACE (a or b) —Cl

ACF (a or b) —F

ACG (a or b) —CF₃

ACH (a or b) —CH₃

ACI (a or b) —Cl

ACJ (a or b) —F

ACK (a or b) —CF₃

ACL (a or b) —CH₃

ACM (a or b) —Cl

ACN (a or b) —F

ACO (a or b) —CF₃

ACP (a or b) —CH₃

ACQ (a or b) —Cl

ACR (a or b) —F

ACS (a or b) —CF₃

ACT (a or b) —CH₃

ACU (a or b) —Cl

ACV (a or b) —F

ACW (a or b) —CF₃

ACX (a or b) —CH₃

ACY (a or b) —Cl

ACZ (a or b) —F

ADA (a orb) —CF₃

ADB (a or b) —CH₃

ADC (a or b) —Cl

ADD (a or b) —F

ADE (a or b) —CF₃

ADF (a or b) —CH₃

TABLE 4 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U BAA (a or b) —Cl

BAB (a or b) —F

BAG (a or b) —CF₃

BAD (a or b) —CH₃

BAE (a or b) —Cl

BAF (a or b) —F

BAG (a or b) —CF₃

BAH (a or b) —CH₃

BAI (a or b) —Cl

BAJ (a or b) —F

BAK (a or b) —CF₃

BAL (a or b) —CH₃

BAM (a or b) —Cl

BAN (a or b) —F

BAO (a or b) —CF₃

BAP (a or b) —CH₃

BAQ (a or b) —Cl

BAR (a or b) —F

BAS (a or b) —CF₃

BAT (a or b) —CH₃

BAU (a or b) —Cl

BAV (a or b) —F

BAW (a or b) —CF₃

BAX (a or b) —CH₃

BAY (a or b) —Cl

BAZ (a or b) —F

BBA (a or b) —CF₃

BBB (a or b) —CH₃

TABLE 5 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U BBC (a or b) —Cl

BBD (a or b) —F

BBE (a or b) —CF₃

BBF (a or b) —CH₃

BBG (a or b) —Cl

BBH (a or b) —F

BBI (a or b) —CF₃

BBJ (a or b) —CH₃

BBK (a or b) —Cl

BBL (a or b) —F

BBM (a or b) —CF₃

BBN (a or b) —CH₃

BBO (a or b) —Cl

BBP(a or b) —F

BBQ (a or b) —CF₃

BBR (a or b) —CH₃

BBS (a or b) —Cl

BBT (a or b) —F

BBU (a or b) —CF₃

BBV (a or b) —CH₃

BBW (a or b) —Cl

BBX (a or b) —F

BBY (a or b) —CF₃

BBZ (a or b) —CH₃

BCA (a or b) —Cl

BCB (a or b) —F

BCC (a or b) —CF₃

BCD (a or b) —CH₃

TABLE 6 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CAA (a or b) —Cl

CAB (a or b) —F

CAC (a or b) —CF₃

CAD (a or b) —CH₃

CAE (a or b) —Cl

CAF (a or b) —F

CAG (a or b) —CF₃

CAH (a or b) —CH₃

CAI (a or b) —Cl

CAJ (a or b) —F

CAK (a or b) —CF₃

CAL (a or b) —CH₃

CAM (a or b) —Cl

CAN(a or b) —F

CAO (a or b) —CF₃

CAP (a or b) —CH₃

CAQ (a or b) —Cl

CAR (a or b) —F

CAS (a or b) —CF₃

CAT (a or b) —CH₃

CAU (a or b) —Cl

CAV (a or b) —F

CAW (a or b) —CF₃

CAX (a or b) —CH₃

CAY (a or b) —Cl

CAZ (a or b) —F

CBA (a or b) —CF₃

CBB (a or b) —CH₃

TABLE 7 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CBC (a or b) —Cl

CBD (a or b) —F

CBE (a or b) —CF₃

CBF (a or b) —CH₃

CBG (a or b) —Cl

CBH (a or b) —F

CBI (a or b) —CF₃

CBJ (a or b) —CH₃

CBK (a or b) —Cl

CBL (a or b) —F

CBM (a or b) —CF₃

CBN (a or b) —CH₃

CBO (a or b) —Cl

CBP (a or b) —F

CBQ (a or b) —CF₃

CBR (a or b) —CH₃

CBS (a or b) —Cl

CRT (a or b) —F

CBU (a or b) —CF₃

CBV (a or b) —CH₃

CBW (a or b) —Cl

CBX (a or b) —F

CBY (a or b) —CF₃

CBZ (a or b) —CH₃

CCA (a or b) —Cl

CCB (a or b) —F

CCD (a or b) —CF₃

CCE (a or b) —CH₃

TABLE 8 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CCF (a or b) —Cl

CCG (a or b) —F

CCH (a or b) —CF₃

CCI (a or b) —CH₃

CCJ (a or b) —Cl

CCK (a or b) —F

CCL (a or b) —CF₃

CCM (a or b) —CH₃

CCN (a or b) —Cl

CCO (a or b) —F

CCP (a or b) —CF₃

CCQ (a or b) —CH₃

CCR (a or b) —Cl

CCS (a or b) —F

CCT (a or b) —CF₃

CCU (a or b) —CH₃

CCV (a or b) —Cl

CCW (a or b) —F

CCX (a or b) —CF₃

CCY (a or b) —CH₃

CCZ (a or b) —Cl

CDA (a or b) —F

CDB (a or b) —CF₃

CDD (a or b) —CH₃

CDE (a or b) —Cl

CDF (a or b) —F

CDG (a or b) —CF₃

CDH (a or b) —CH₃

TABLE 9 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CDI (a or b) —Cl

CDJ (a or b) —F

CDK (a or b) —CF₃

CDL (a or b) —CH₃

CDM (a or b) —Cl

CDN (a or b) —F

CDO (a or b) —CF₃

CDP (a or b) —CH₃

CDQ (a or b) —Cl

CDR (a or b) —F

CDS (a or b) —CF₃

CDT (a or b) —CH₃

CDU (a or b) —Cl

CDV (a or b) —F

CDW (a or b) —CF₃

CDX (a or b) —CH₃

CDY (a or b) —Cl

CDZ (a or b) —F

CEA (a or b) —CF₃

CEB (a or b) —CH₃

CEC (a or b) —Cl

CED (a or b) —F

CEE (a or b) —CF₃

CEF (a or b) —CH₃

CEG (a or b) —Cl

CEH (a or b) —F

CEI (a or b) —CF₃

CEJ (a or b) —CH₃

TABLE 10 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CEK (a or b) —Cl

CEL (a or b) —F

CEM (a or b) —CF₃

CEN (a or b) —CH₃

CEO (a or b) —Cl

CEP (a or b) —F

CEQ (a or b) —CF₃

CER (a or b) —CH₃

CES (a or b) —Cl

CET (a or b) —F

CEU (a or b) —CF₃

CEV (a or b) —CH₃

CEW (a or b) —Cl

CEX (a or b) —F

CEY (a or b) —CF₃

CEZ (a or b) —CH₃

CFA (a or b) —Cl

CFB (a or b) —F

CFC (a or b) —CF₃

CFD (a or b) —CH₃

CFE (a or b) —Cl

CFF (a or b) —F

CFG (a or b) —CF₃

CFH (a or b) —CH₃

CFI (a or b) —Cl

CFJ (a or b) —F

CFK (a or b) —CF₃

CFL (a or b) —CH₃

TABLE 11 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CFM (a or b) —Cl

CFN (a or b) —F

CFO (a or b) —CF₃

CFP (a or b) —CH₃

CFQ (a or b) —Cl

CFR (a or b) —F

CFS (a or b) —CF₃

CFT (a or b) —CH₃

CFU (a or b) —Cl

CFV (a or b) —F

CFW (a or b) —CF₃

CFX (a or b) —CH₃

CFY (a or b) —Cl

CFZ (a or b) —F

CGA (a or b) —CF₃

CGB (a or b) —CH₃

CGC (a or b) —Cl

CGD (a or b) —F

CCE (a or b) —CF₃

CGF (a or b) —CH₃

CGG (a or b) —Cl

CGH (a or b) —F

CGI (a or b) —CF₃

CGJ (a or b) —CH₃

CGK (a or b) —Cl

CGL (a or b) —F

CGM (a or b) —CF₃

CGN (a or b) —CH₃

TABLE 12 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CGO (a or b) —Cl

CGP (a or b) —F

CGQ (a or b) —CF₃

CGR (a or b) —CH₃

CGS (a or b) —Cl

CGT (a or b) —F

CGU (a or b) —CF₃

CGV (a or b) —CH₃

CGW (a or b) —Cl

CGX (a or b) —F

CGY (a or b) —CF₃

CGZ (a or b) —CH₃

CHA (a or b) —Cl

CHB (a or b) —F

CHC (a or b) —CF₃

CHD (a or b) —CH₃

CHE (a or b) —Cl

CHF (a or b) —F

CHG (a or b) —CF₃

CHH (a or b) —CH₃

CHI (a or b) —Cl

CHJ (a or b) —F

CHK (a or b) —CF₃

CHL (a or b) —CH₃

CHM (a or b) —Cl

CHN (a or b) —F

CHO (a or b) —CF₃

CHP (a or b) —CH₃

TABLE 13 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CIA (a or b) —Cl

CIB (a or b) —F

CIC (a or b) —CF₃

CID (a or b) —CH₃

CIE (a or b) —Cl

CIF (a or b) —F

CIG (a or b) —CF₃

CIH (a or b) —CH₃

CII (a or b) —Cl

CIJ (a or b) —F

CIK (a or b) —CF₃

CIL (a or b) —CH₃

CIM (a or b) —Cl

CIN (a or b) —F

CIO (a or b) —CF₃

CIP (a or b) —CH₃

CIQ (a or b) —Cl

CIR (a or b) —F

CIS (a or b) —CF₃

CIT (a or b) —CH₃

CIU (a or b) —Cl

CIV (a or b) —F

CIW (a or b) —CF₃

CIX (a or b) —CH₃

CIY (a or b) —Cl

CIZ (a or b) —F

CJA (a or b) —CF₃

CJB (a or b) —CH₃

TABLE 14 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CKA (a or b) —Cl

CKB (a or b) —F

CKC (a or b) —CF₃

CKD (a or b) —CH₃

CKE (a or b) —Cl

CKF (a or b) —F

CKG (a or b) —CF₃

CKH (a or b) —CH₃

CKI (a or b) —Cl

CKJ (a or b) —F

CKK (a or b) —CF₃

CKL (a or b) —CH₃

CKM (a or b) —Cl

CKN (a or b) —F

CKO (a or b) —CF₃

CKP (a or b) —CH₃

CKQ (a or b) —Cl

CKR (a or b) —F

CKS (a or b) —CF₃

CKT (a or b) —CH₃

CKU (a or b) —Cl

CKV (a or b) —F

CKW (a or b) —CF₃

CKX (a or b) —CH₃

CKY (a or b) —Cl

CKZ (a or b) —F

CLA (a or b) —CF₃

CLB (a or b) —CH₃

TABLE 15 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CMA (a or b) —Cl

CMB (a or b) —F

CMC (a or b) —CF₃

CMD (a or b) —CH₃

CME (a or b) —Cl

CME (a or b) —F

CMG (a or b) —CF₃

CMH (a or b) —CH₃

CMI (a or b) —Cl

CMJ (a or b) —F

CMK (a or b) —CF₃

CML (a or b) —CH₃

CMM (a or b) —Cl

CMN (a or b) —F

CMO (a or b) —CF₃

CMP (a or b) —CH₃

CMQ (a or b) —Cl

CMR (a or b) —F

CMS (a or b) —CF₃

CMT (a or b) —CH₃

CMU (a or b) —Cl

CMV (a or b) —F

CMW (a or b) —CF₃

CMX (a or b) —CH₃

CMY (a or b) —Cl

CMZ (a or b) —F

CNA (a or b) —CF₃

CNB (a or b) —CH₃

TABLE 16 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U COA (a or b) —Cl

COB (a or b) —F

COC (a or b) —CF₃

COD (a or b) —CH₃

COE (a or b) —Cl

COF (a or b) —F

COG (a or b) —CF₃

COH (a or b) —CH₃

COI (a or b) —Cl

COJ (a or b) —F

COK (a or b) —CF₃

COL (a or b) —CH₃

COM (a or b) —Cl

CON (a or b) —F

COO (a or b) —CF₃

COP (a or b) —CH₃

COQ (a or b) —Cl

COR (a or b) —F

COS (a or b) —CF₃

COT (a or b) —CH₃

COU (a or b) —Cl

COV (a or b) —F

COW (a or b) —CF₃

COX (a or b) —CH₃

COY (a or b) —Cl

COZ (a or b) —F

CPA (a or b) —CF₃

CPB (a or b) —CH₃

TABLE 17 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CQA (a or b) —Cl

CQB (a or b) —F

CQC (a or b) —CF₃

CQD (a or b) —CH₃

CQE (a or b) —Cl

CQF (a or b) —F

CQG (a or b) —CF₃

CQH (a or b) —CH₃

CQI (a or b) —Cl

CQJ (a or b) —F

CQK (a or b) —CF₃

CQL (a or b) —CH₃

CQM (a or b) —Cl

CQN (a or b) —F

CQO (a or b) —CF₃

CQP (a or b) —CH₃

CQQ (a or b) —Cl

CQR (a or b) —F

CQS (a or b) —CF₃

CQT (a or b) —CH₃

CQU (a or b) —Cl

CQV (a or b) —F

CQW (a or b) —CF₃

CQX (a or b) —CH₃

CQY (a or b) —Cl

CQZ (a or b) —F

CRA (a or b) —CF₃

CRB (a or b) —CH₃

TABLE 18 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CSA (a or b) —Cl

CSB (a or b) —F

CSC (a or b) —CF₃

CSD (a or b) —CH₃

CSE (a or b) —Cl

CSF (a or b) —F

CSG (a or b) —CF₃

CSH (a or b) —CH₃

CSI (a or b) —Cl

CSJ (a or b) —F

CSK (a or b) —CF₃

CSL (a or b) —CH₃

CSM (a or b) —Cl

CSN (a or b) —F

CS (═O) (a or b) —CF₃

CSP (a or b) —CH₃

CSQ (a or b) —Cl

CSR (a or b) —F

CSS (a or b) —CF₃

CST (a or b) —CH₃

CSU (a or b) —Cl

CSV (a or b) —F

CSW (a or b) —CF₃

CSX (a or b) —CH₃

CSY (a or b) —Cl

CSZ (a or b) —F

CTA (a or b) —CF₃

CTB (a or b) —CH₃

TABLE 19 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CUA (a or b) —Cl

CUB (a or b) —F

CUC (a or b) —CF₃

CUD (a or b) —CH₃

CUE (a or b) —Cl

CUE (a or b) —F

CUG (a or b) —CF₃

CUH (a or b) —CH₃

CUI (a or b) —Cl

CUJ (a or b) —F

CUK (a or b) —CF₃

CUL (a or b) —CH₃

CUM (a or b) —Cl

CUN (a or b) —F

CUO (a or b) —CF₃

CUP (a or b) —CH₃

CUQ (a or b) —Cl

CUR (a or b) —F

CUS (a or b) —CF₃

CUT (a or b) —CH₃

CUU (a or b) —Cl

CUV (a or b) —F

CUW (a or b) —CF₃

CUX (a or b) —CH₃

CUY (a or b) —Cl

CUZ (a or b) —F

CVA (a or b) —CF₃

CVB (a or b) —CH₃

TABLE 20 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CWA (a or b) —Cl

CWB (a or b) —F

CWC (a or b) —CF₃

CWD (a or b) —CH₃

CWE (a or b) —Cl

CWF (a or b) —F

CWG (a or b) —CF₃

CWH (a or b) —CH₃

CWI (a or b) —Cl

CWJ (a or b) —F

CWK (a or b) —CF₃

CWL (a or b) —CH₃

CWM (a or b) —Cl

CWN (a or b) —F

CWO (a or b) —CF₃

CWP (a or b) —CH₃

CWQ (a or b) —Cl

CWR (a or b) —F

CWS (a or b) —CF₃

CWT (a or b) —CH₃

CWU (a or b) —Cl

CWV (a or b) —F

CWW (a or b) —CF₃

CWX (a or b) —CH₃

CWY (a or b) —Cl

CWZ (a or b) —F

CXA (a or b) —CF₃

CXB (a or b) —CH₃

TABLE 21 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U CYA (a or b) —Cl

CYB (a or b) —F

CYC (a or b) —CF₃

CYD (a or b) —CH₃

CYE (a or b) —Cl

CYF (a or b) —F

CYG (a or b) —CF₃

CYH (a or b) —CH₃

CYI (a or b) —Cl

CYJ (a or b) —F

CYK (a or b) —CF₃

CYL (a or b) —CH₃

CYM (a or b) —Cl

CYN (a or b) —F

CYO (a or b) —CF₃

CYP (a or b) —CH₃

CYQ (a or b) —Cl

CYR (a or b) —F

CYS (a or b) —CF₃

CYT (a or b) —CH₃

CYU (a or b) —Cl

CYV (a or b) —F

CYW (a or b) —CF₃

CYX (a or b) —CH₃

CYY (a or b) —Cl

CYZ (a or b) —F

CZA (a or b) —CF₃

CZB (a or b) —CH₃

TABLE 22 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DAA (a or b) —Cl

DAB (a or b) —F

DAC (a or b) —CF₃

DAD (a or b) —CH₃

DAE (a or b) —Cl

DAF (a or b) —F

DAG (a or b) —CF₃

DAH (a or b) —CH₃

DAI (a or b) —Cl

DAJ (a or b) —F

DAK (a or b) —CF₃

DAL (a or b) —CH₃

DAM (a or b) —Cl

DAN (a or b) —F

DAO (a or b) —CF₃

DAP (a or b) —CH₃

DAQ (a or b) —Cl

DAR (a or b) —F

DAS (a or b) —CF₃

DAT (a or b) —CH₃

DAU (a or b) —Cl

DAV (a or b) —F

DAW (a or b) —CF₃

DAX (a or b) —CH₃

DAY (a or b) —Cl

DAZ (a or b) —F

DBA (a or b) —CF₃

DBB (a or b) —CH₃

TABLE 23 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DCA (a or b) —Cl

DCB (a or b) —F

DCC (a or b) —CF₃

DCD (a or b) —CH₃

DCE (a or b) —Cl

DCF (a or b) —F

DCG (a or b) —CF₃

DCH (a or b) —CH₃

DCI (a or b) —Cl

DCJ (a or b) —F

DCK (a or b) —CF₃

DCL (a or b) —CH₃

DCM (a or b) —Cl

DCN (a or b) —F

DCO (a or b) —CF₃

DCP (a or b) —CH₃

DCQ (a or b) —Cl

DCR (a or b) —F

DCS (a or b) —CF₃

DCT (a or b) —CH₃

DCU (a or b) —Cl

DCV (a or b) —F

DCW (a or b) —CF₃

DCX (a or b) —CH₃

DCY (a or b) —Cl

DCZ (a or b) —F

DDA (a or b) —CF₃

DDB (a or b) —CH₃

TABLE 24 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DEA (a or b) —Cl

DEB (a or b) —F

DEC (a or b) —CF₃

DED (a or b) —CH₃

DEE (a or b) —Cl

DEF (a or b) —F

DEG (a or b) —CF₃

DEH (a or b) —CH₃

DEI (a or b) —Cl

DEJ (a or b) —F

DEK (a or b) —CF₃

DEL (a or b) —CH₃

DEM (a or b) —Cl

DEN (a or b) —F

DEO (a or b) —CF₃

DEP (a or b) —CH₃

DEQ (a or b) —Cl

DER (a or b) —F

DES (a or b) —CF₃

DET (a or b) —CH₃

DEU (a or b) —Cl

DEV (a or b) —F

DEW (a or b) —CF₃

DEX (a or b) —CH₃

DEY (a or b) —Cl

DEZ (a or b) —F

DFA (a or b) —CF₃

DFB (a or b) —CH₃

TABLE 25 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DGA (a or b) —Cl

DGB (a or b) —F

DGC (a or b) —CF₃

DGD (a or b) —CH₃

DGE (a or b) —Cl

DGF (a or b) —F

DGG (a or b) —CF₃

DGH (a or b) —CH₃

DGI (a or b) —Cl

DGJ (a or b) —F

DGK (a or b) —CF₃

DGL (a or b) —CH₃

DGM (a or b) —Cl

DGN (a or b) —F

DGO (a or b) —CF₃

DGP (a or b) —CH₃

DGQ (a or b) —Cl

DGR (a or b) —F

DGS (a or b) —CF₃

DGT (a or b) —CH₃

DGU (a or b) —Cl

DGV (a or b) —F

DGW (a or b) —CF₃

DGX (a or b) —CH₃

DGY (a or b) —Cl

DGZ (a or b) —F

DHA (a or b) —CF₃

DHB (a or b) —CH₃

TABLE 26 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DIA (a or b) —Cl

DIB (a or b) —F

DIC (a or b) —CF₃

DID (a or b) —CH₃

DIE (a or b) —Cl

DIF (a or b) —F

DIG (a or b) —CF₃

DIH (a or b) —CH₃

DII (a or b) —Cl

DIJ (a or b) —F

DIK (a or b) —CF₃

DIL (a or b) —CH₃

DIM (a or b) —Cl

DIN (a or b) —F

DIO (a or b) —CF₃

DIP (a or b) —CH₃

DIQ (a or b) —Cl

DIR (a or b) —F

DIS (a or b) —CF₃

DIT (a or b) —CH₃

DIU (a or b) —Cl

DIV (a or b) —F

DIW (a or b) —CF₃

DIX (a or b) —CH₃

DIY (a or b) —Cl

DIZ (a or b) —F

DJA (a or b) —CF₃

DJB (a or b) —CH₃

TABLE 27 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DKA (a or b) —Cl

DKB (a or b) —F

DKC (a or b) —CF₃

DKD (a or b) —CH₃

DKE (a or b) —Cl

DKF (a or b) —F

DKG (a or b) —CF₃

DKH (a or b) —CH₃

DKI (a or b) —Cl

DKJ (a or b) —F

DKK (a or b) —CF₃

DKL (a or b) —CH₃

DKM (a or b) —Cl

DKN (a or b) —F

DKO (a or b) —CF₃

DKP (a or b) —CH₃

DKQ (a or b) —Cl

DKR (a or b) —F

DKS (a or b) —CF₃

DKT (a or b) —CH₃

DKU (a or b) —Cl

DKV (a or b) —F

DKW (a or b) —CF₃

DKX (a or b) —CH₃

DKY (a or b) —Cl

DKZ (a or b) —F

DLA (a or b) —CF₃

DLB (a or b) —CH₃

TABLE 28 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DMA (a or b) —Cl

DMB (a or b) —F

DMC (a or b) —CF₃

DMD (a or b) —CH₃

DME (a or b) —Cl

DMF (a or b) —F

DMG (a or b) —CF₃

DMH (a or b) —CH₃

DMI (a or b) —Cl

DMJ (a or b) —F

DMK (a or b) —CF₃

DML (a or b) —CH₃

DMM (a or b) —Cl

DMN (a or b) —F

DMO (a or b) —CF₃

DMP (a or b) —CH₃

DMQ (a or b) —Cl

DMR (a or b) —F

DMS (a or b) —CF₃

DMT (a or b) —CH₃

DMU (a or b) —Cl

DMV (a or b) —F

DMW (a or b) —CF₃

DMX (a or b) —CH₃

DMY (a or b) —Cl

DMZ (a or b) —F

DNA (a or b) —CF₃

DNB (a or b) —CH₃

TABLE 29 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DOA (a or b) —Cl

DOB (a or b) —F

DOC (a or b) —CF₃

DOD (a or b) —CH₃

DOE (a or b) —Cl

DOF (a or b) —F

DOG (a or b) —CF₃

DOH (a or b) —CH₃

DOI (a or b) —Cl

DOJ (a or b) —F

DOK (a or b) —CF₃

DOL (a or b) —CH₃

DOM (a or b) —Cl

DON (a or b) —F

DOO (a or b) —CF₃

DOP (a or b) —CH₃

DOQ (a or b) —Cl

DOR (a or b) —F

DOS (a or b) —CF_(3 I)

DOT (a or b) —CH₃

DOU (a or b) —Cl

DOV (a or b) —F

DOW (a or b) —CF₃

DOX (a or b) —CH₃

DOY (a or b) —Cl

DOZ (a or b) —F

DPA (a or b) —CF₃

DPB (a or b) —CH₃

TABLE 30 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DQA (a or b) —Cl

DQB (a or b) —F

DQC (a or b) —CF₃

DQD (a or b) —CH₃

DQE (a or b) —Cl

DQF (a or b) —F

DQG (a or b) —CF₃

DQH (a or b) —CH₃

DQI (a or b) —Cl

DQJ (a or b) —F

DQK (a or b) —CF₃

DQL (a or b) —CH₃

DQM (a or b) —Cl

DQN (a or b) —F

DQO (a or b) —CF₃

DQP (a or b) —CH₃

DQQ (a or b) —Cl

DQR (a or b) —F

DQS (a or b) —CF₃

DQT (a or b) —CH₃

DQU (a or b) —Cl

DQV (a or b) —F

DQW (a or b) —CF₃

DQX (a or b) —CH₃

DQY (a or b) —Cl

DQZ (a or b) —F

DRA (a or b) —CF₃

DRB (a or b) —CH₃

TABLE 31 (a)

(b)

and pharmaceutically acceptable derivatives thereof where: Compound R₁ UDSA (a or b) —Cl

DSB (a or b) —F

DSC (a or b) —CF₃

DSD (a or b) —CH₃

DSE (a or b) —Cl

DSF (a or b) —F

DSG (a or b) —CF₃

DSH (a or b) —CH₃

DSI (a or b) —Cl

DSJ (a or b) —F

DSK (a or b) —CF₃

DSL (a or b) —CH₃

DSM (a or b) —Cl

DSN (a or b) —F

DS(═O) (a or b) —CF₃

DSP (a or b) —CH₃

DSQ (a or b) —Cl

DSR (a or b) —F

DSS (a or b) —CF₃

DST (a or b) —CH₃

DSU (a or b) —Cl

DSV (a or b) —F

DSW (a or b) —CF₃

DSX (a or b) —CH₃

DSY (a or b) —Cl

DSZ (a or b) —F

DTA (a or b) —CF₃

DTB (a or b) —CH₃

TABLE 32 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DUA (a or b) —Cl

DUB (a or b) —F

DUC (a or b) —CF₃

DUD (a or b) —CH₃

DUE (a or b) —Cl

DUF (a or b) —F

DUG (a or b) —CF₃

DUH (a or b) —CH₃

DUI (a or b) —Cl

DUJ (a or b) —F

DUK (a or b) —CF₃

DUL (a or b) —CH₃

DUM (a or b) —Cl

DUN (a or b) —F

DUO (a or b) —CF₃

DUP (a or b) —CH₃

DUQ (a or b) —Cl

DUR (a or b) —F

DUS (a or b) —CF₃

DUT (a or b) —CH₃

DUU (a or b) —Cl

DUV (a or b) —F

DUW (a or b) —CF₃

DUX (a or b) —CH₃

DUY (a or b) —Cl

DUZ (a or b) —F

DVA (a or b) —CF₃

DVB (a or b) —CH₃

TABLE 33 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DWA (a or b) —Cl

DWB (a or b) —F

DWC (a or b) —CF₃

DWD (a or b) —CH₃

DWE (a or b) —Cl

DWF (a or b) —F

DWG (a or b) —CF₃

DWH (a or b) —CH₃

DWI (a or b) —Cl

DWJ (a or b) —F

DWK (a or b) —CF₃

DWL (a or b) —CH₃

DWM (a or b) —Cl

DWN (a or b) —F

DWO (a or b) —CF₃

DWP (a or b) —CH₃

DWQ (a or b) —Cl

DWR (a or b) —F

DWS (a or b) —CF₃

DWT (a or b) —CH₃

DWU (a or b) —Cl

DWV (a or b) —F

DWW (a or b) —CF₃

DWX (a or b) —CH₃

DWY (a or b) —Cl

DWZ (a or b) —F

DXA (a or b) —CF₃

DXB (a or b) —CH₃

TABLE 34 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U DYA (a or b) —Cl

DYB (a or b) —F

DYC (a or b) —CF₃

DYD (a or b) —CH₃

DYE (a or b) —Cl

DYF (a or b) —F

DYG (a or b) —CF₃

DYH (a or b) —CH₃

DYI (a or b) —Cl

DYJ (a or b) —F

DYK (a or b) —CF₃

DYL (a or b) —CH₃

DYM (a or b) —Cl

DYN (a or b) —F

DYO (a or b) —CF₃

DYP (a or b) —CH₃

DYQ (a or b) —Cl

DYR (a or b) —F

DYS (a or b) —CF₃

DYT (a or b) —CH₃

DYU (a or b) —Cl

DYV (a or b) —F

DYW (a or b) —CF₃

DYX (a or b) —CH₃

DYY (a or b) —Cl

DYZ (a or b) —F

DZA (a or b) —CF₃

DZB (a or b) —CH₃

TABLE 35 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U EAA (a or b) —Cl

EAB (a or b) —F

EAC (a or b) —CF₃

EAD (a or b) —CH₃

EAE (a or b) —Cl

EAF (a or b) —F

EAG (a or b) —CF₃

EAH (a or b) —CH₃

EAI (a or b) —Cl

EAJ (a or b) —F

EAK (a or b) —CF₃

EAL (a or b) —CH₃

EAM (a or b) —Cl

EAN (a or b) —F

EAO (a or b) —CF₃

EAP (a or b) —CH₃

EAQ (a or b) —Cl

EAR (a or b) —F

EAS (a or b) —CF₃

EAT (a or b) —CH₃

EAU (a or b) —Cl

EAV (a or b) —F

EAW (a or b) —CF₃

EAX (a or b) —CH₃

EAY (a or b) —Cl

EAZ (a or b) —F

EBA (a or b) —CF₃

EBB (a or b) —CH₃

TABLE 36 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ECA (a or b) —Cl

ECB (a or b) —F

ECC (a or b) —CF₃

ECD (a or b) —CH₃

ECE (a or b) —Cl

ECF (a or b) —F

ECG (a or b) —CF₃

ECH (a or b) —CH₃

ECI (a or b) —Cl

ECJ (a or b) —F

ECK (a or b) —CF₃

ECL (a or b) —CH₃

ECM (a or b) —Cl

ECN (a or b) —F

a ECO (a or b) —CF₃

ECP (a or b) —CH₃

ECQ (a or b) —Cl

ECR (a or b) —F

ECS (a or b) —CF₃

ECT (a or b) —CH₃

ECU (a or b) —Cl

ECV (a or b) —F

ECW (a or b) —CF₃

ECX (a or b) —CH₃

ECY (a or b) —Cl

ECZ (a or b) —F

EDA (a or b) —CF₃

EDB (a or b) —CH₃

TABLE 37 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U EEA (a or b) —Cl

EEB (a or b) —F

EEC (a or b) —CF₃

EED (a or b) —CH₃

EEE (a or b) —Cl

EEF (a or b) —F

EEG (a or b) —CF₃

EEH (a or b) —CH₃

EEI (a or b) —Cl

EEJ (a or b) —F

EEK (a or b) —CF₃

EEL (a or b) —CH₃

EEM (a or b) —Cl

EEN (a or b) —F

EEO (a or b) —CF₃

EEP (a or b) —CH₃

EEQ (a or b) —Cl

EER (a or b) —F

EES (a or b) —CF₃

EET (a or b) —CH₃

EEU (a or b) —Cl

EEV (a or b) —F

EEW (a or b) —CF₃

EEX (a or b) —CH₃

EEY (a or b) —Cl

EEZ (a or b) —F

EFA (a or b) —CF₃

EFB (a or b) —CH₃

TABLE 38 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U EGA (a or b) —Cl

EGB (a or b) —F

EGC (a or b) —CF₃

EGD (a or b) —CH₃

EGE (a or b) —Cl

EGF (a or b) —F

EGG (a or b) —CF₃

EGH (a or b) —CH₃

EGI (a or b) —Cl

EGJ (a or b) —F

EGK (a or b) —CF₃

EGL (a or b) —CH₃

EGM (a or b) —Cl

EGN (a or b) —F

EGO (a or b) —CF₃

EGP (a or b) —CH₃

EGQ (a or b) —Cl

EGR (a or b) —F

EGS (a or b) —CF₃

EGT (a or b) —CH₃

EGU (a or b) —Cl

EGV (a or b) —F

EGW (a or b) —CF₃

EGX (a or b) —CH₃

EGY (a or b) —Cl

EGZ (a or b) —F

EHA (a or b) —CF₃

EHB (a or b) —CH₃

TABLE 39 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U EJA (a or b) —Cl

EJB (a or b) —F

EJC (a or b) —CF₃

EJD (a or b) —CH₃

EJE (a or b) —Cl

EJF (a or b) —F

EJG (a or b) —CF₃

EJH (a or b) —CH₃

EJI (a or b) —Cl

EJJ (a or b) —F

EJK (a or b) —CF₃

EJL (a or b) —CH₃

EJM (a or b) —Cl

EJN (a or b) —F

EJO (a or b) —CF₃

EJP (a or b) —CH₃

EJQ (a or b) —Cl

EJR (a or b) —F

EJS (a or b) —CF₃

EJT (a or b) —CH₃

EJU (a or b) —Cl

EJV (a or b) —F

EJW (a or b) —CF₃

EJX (a or b) —CH₃

EJY (a or b) —Cl

EJZ (a or b) —F

EKA (a or b) —CF₃

EKB (a or b) —CH₃

TABLE 40 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ELA (a or b) —Cl

ELB (a or b) —F

ELC (a or b) —CF₃

ELD (a or b) —CH₃

ELE (a or b) —Cl

ELF (a or b) —F

ELG (a or b) —CF₃

ELH (a or b) —CH₃

ELI (a or b) —Cl

ELJ (a or b) —F

ELK (a or b) —CF₃

ELL (a or b) —CH₃

ELM (a or b) —Cl

ELN (a or b) —F

ELO (a or b) —CF₃

ELP (a or b) —CH₃

ELQ (a or b) —Cl

ELR (a or b) —F

ELS (a or b) —CF₃

ELT (a or b) —CH₃

ELU (a or b) —Cl

ELV (a or b) —F

ELW (a or b) —CF₃

ELX (a or b) —CH₃

ELY (a or b) —Cl

ELZ (a or b) —F

EMA (a or b) —CF₃

EMB (a or b) —CH₃

TABLE 41 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ENA (a or b) —Cl

ENB (a or b) —F

ENC (a or b) —CF₃

END (a or b) —CH₃

ENE (a or b) —Cl

ENF (a or b) —F

ENG (a or b) —CF₃

ENH (a or b) —CH₃

ENI (a or b) —Cl

ENJ (a or b) —F

ENK (a or b) —CF₃

ENL (a or b) —CH₃

ENM (a or b) —Cl

ENN (a or b) —F

ENO (a or b) —CF₃

ENP (a or b) —CH₃

ENQ (a or b) —Cl

ENR (a or b) —F

ENS (a or b) —CF₃

ENT (a or b) —CH₃

ENU (a or b) —Cl

ENV (a or b) —F

ENW (a or b) —CF₃

ENX (a or b) —CH₃

ENY (a or b) —Cl

ENZ (a or b) —F

EOA (a or b) —CF₃

EOB (a or b) —CH₃

TABLE 42 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U EPA (a or b) —Cl

EPB (a or b) —F

EPC (a or b) —CF₃

EPD (a or b) —CH₃

EPE (a or b) —Cl

EPF (a or b) —F

EPG (a or b) —CF₃

EPH (a or b) —CH₃

EPI (a or b) —Cl

EPJ (a or b) —F

EPK (a or b) —CF₃

EPL (a or b) —CH₃

EPM (a or b) —Cl

EPN (a or b) —F

EPO (a or b) —CF₃

EPP (a or b) —CH₃

EPQ (a or b) —Cl

EPR (a or b) —F

EPS (a or b) —CF₃

EPT (a or b) —CH₃

EPU (a or b) —Cl

EPV (a or b) —F

EPW (a or b) —CF₃

EPX (a or b) —CH₃

EPY (a or b) —Cl

EPZ (a or b) —F

EQA (a or b) —CF₃

EQB (a or b) —CH₃

TABLE 43 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ERA (a or b) —Cl

ERB (a or b) —F

ERC (a or b) —CF₃

ERD (a or b) —CH₃

ERE (a or b) —Cl

ERF (a or b) —F

ERG (a or b) —CF₃

ERH (a or b) —CH₃

ERI (a or b) —Cl

ERJ (a or b) —F

ERK (a or b) —CF₃

ERL (a or b) —CH₃

ERM (a or b) —Cl

ERN (a or b) —F

ERO (a or b) —CF₃

ERP (a or b) —CH₃

ERQ (a or b) —Cl

ERR (a or b) —F

ERS (a or b) —CF₃

ERT (a or b) —CH₃

ERU (a or b) —Cl

ERV (a or b) —F

ERW (a or b) —CF₃

ERX (a or b) —CH₃

ERY (a or b) —Cl

ERZ (a or b) —F

ESA (a or b) —CF₃

ESB (a or b) —CH₃

TABLE 44 (a)

(b)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁U ESC (a or b) —Cl

ESD (a or b) —F

ESE (a or b) —CF₃

ESF (a or b) —CH₃

ESG (a or b) —Cl

ESH (a or b) —F

ESI (a or b) —CF₃

ESJ (a or b) —CH₃

ESK (a or b) —Cl

ESL (a or b) —F

ESM (a or b) —CF₃

ESN (a or b) —CH₃

ES(═O) (a or b) —Cl

ESP (a or b) —F

ESQ (a or b) —CF₃

ESR (a or b) —CH₃

ESS (a or b) —Cl

EST (a or b) —F

ESU (a or b) —CF₃

ESV (a or b) —CH₃

ESW (a or b) —Cl

ESX (a or b) —F

ESY (a or b) —CF₃

ESZ (a or b) —CH₃

ETA (a or b) —Cl

ETB (a or b) —F

ETC (a or b) —CF₃

ETD (a or b) —CH₃

4.4. DEFINITIONS

As used in connection with the compounds of formulae I-III (e.g.,compounds of formulae I(a), I(b), I(c), I(d), II(a), II(b), II(c),II(d), III(a), III(b), III(c), III(d), III(e), III(f), III(g), III(h),III(i), III(j), III(k) and III(l)) herein, the terms used above havingfollowing meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.Representative branched —(C₁-C₁₀)alkyls include iso-propyl, sec-butyl,iso-butyl, tert-butyl, iso-pentyl, neo-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl,3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl,and n-hexyl. Representative branched —(C₁-C₆)alkyls include iso-propyl,sec-butyl, iso-butyl, tert-butyl, iso-pentyl, neo-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include methyl, ethyl, n-propyl, and n-butyl.Representative branched —(C₁-C₄)alkyls include iso-propyl, sec-butyl,iso-butyl, and tert-butyl.

“—(C₁-C₆)haloalkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms as defined above for—(C₁-C₆)alkyl that is substituted with 1, 2, 3, 4, 5 or 6 independentlyselected -halo groups or where each hydrogen of the —(C₁-C₆)alkyl isreplaced with an independently selected -halo group. Representative(C₁-C₆)haloalkyls include trifluoromethyl, perfluoroethyl,4-bromo-2-fluoro-3-iodobutyl, and1,1,4,4,4-pentaiodo-3-(iodomethyl)-3-methylbutyl.

“—(C₁-C₆)hydroxyalkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms as defined above for—(C₁-C₆)alkyl that is substituted with 1, 2 or 3 hydroxyl groups.Representative —(C₁-C₆)hydroxyalkyls include 1,3-dihydroxybutyl,2-(methyl)-2-(hydroxymethylpropane-1,3-diol, and2-ethyl-2-methyl-propane-1,3-diol.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched—(C₂-C₁₀)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,iso-butylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and3-decenyl.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched—(C₂-C₆)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,iso-butylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, and3-hexenyl.

“—(C₂-C₆)haloalkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond as defined above for —(C₂-C₆)alkenyl that issubstituted with 1, 2 or 3 independently selected -halo groups.Representative —(C₂-C₆)haloalkenyls include 2-(fluoromethyl)but-3-enyl,2-(bromofluoromethyl)but-3-enyl, and 1,1-dichlorobut-3-en-2-yl.

“—(C₂-C₆)hydroxyalkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond as defined above for —(C₂-C₆)alkenyl that issubstituted with 1, 2 or 3 hydroxyl groups. Representative—(C₂-C₆)hydroxyalkenyls include 2-(methyl)-2-vinylpropane-1,3-diol, and2-(methyl)but-3-en-1-ol.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butyryl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, and -9-decynyl.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, and -5-hexynyl.

“—(C₂-C₆)haloalkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond that is substituted with 1, 2 or 3independently selected -halo groups. Representative —(C₂-C₆)haloalkynylsinclude 2-(fluoromethyl)but-3-ynyl, 2-(bromofluoromethyl)but-3-ynyl, and1,1-dichlorobut-3-yn-2-yl.

“—(C₂-C₆)hydroxyalkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond that is substituted with 1, 2 or 3 hydroxylgroups. Representative —(C₂-C₆)hydroxyalkynyls include2-(methyl)-2-ethynyl-propane-1,3-diol, and 2-(methyl)but-3-yn-1-ol.

“—(C₁-C₆)alkoxy” means a straight chain or branched non cyclichydrocarbon having one or more ether groups and from 1 to 6 carbonatoms. Representative straight chain and branched —(C₁-C₆)alkoxysinclude methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy,methoxymethyl, 2-methoxyethyl, 5-methoxypentyl, and 3-ethoxybutyl.

“—(C₁-C₆)alkoxy-(C₂-C₆)alkyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkoxy group that issubstituted with a —(C₂-C₆)alkyl group. Representative—(C₁-C₆)alkoxy-(C₂-C₆)alkyls include2-methyl-3-(3-methylpentan-2-yloxy)butyl,2-methyl-3-(3-methylenepent-4-yn-2-yloxy)butyl,2-methyl-3-(3-methylenepent-4-yn-2-yloxy)butyl, and3-isopropoxy-2-methylbutyl.

“—(C₁-C₆)alkoxy-(C₂-C₆)alkenyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkoxy group that issubstituted with a —(C₂-C₆)alkenyl group. Representative—(C₁-C₆)alkoxy-(C₂-C₆)alkenyls include2-methyl-3-(3-methylenepentan-2-yloxy)butyl,2-methyl-3-(3-methylpent-3-en-2-yloxy)butyl, and2-methyl-3-(3-methylenepent-4-en-2-yloxy)butyl.

“—(C₁-C₆)alkoxy-(C₂-C₆)alkynyl” means a straight chain or branched noncyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms that is substituted with a —(C₂-C₆)alkynyl group.Representative —(C₁-C₆)alkoxy-(C₂-C₆)alkynyls include2-methyl-3-(3-methylenepentan-2-yloxy)butyl,2-methyl-3-(3-methylpent-3-yn-2-yloxy)butyl, and2-methyl-3-(3-methylenepent-4-yn-2-yloxy)butyl.

“—(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyl” means a straight chain or branchednon cyclic hydrocarbon having one or more ether groups and from 1 to 6carbon atoms as defined above for —(C₁-C₆)alkyl group that issubstituted with a —(C₃-C₈)cycloalkyl group. Representative—(C₁-C₆)alkoxy-(C₃-C₈)cycloalkyls include 3-(cyclohexyloxy)butyl,1-cyclopropoxypentan-3-yl, and 1-(2-cyclopropylethoxy)propyl,(cyclopentylmethoxy)(methoxy)methyl.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative —(C₃-C₁₀)cycloalkyls are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, and cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative —(C₃-C₈)cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₈-C₁₄)bicycloalkyls include indanyl,1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydronaphthyl, andperhydronaphthyl.

“—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated ring.Representative —(C₈-C₁₄)tricycloalkyls include pyrenyl,1,2,3,4-tetrahydroanthracenyl, perhydroanthracenyl aceanthreneyl,1,2,3,4-tetrahydropenanthrenyl, 5,6,7,8-tetrahydrophenanthrenyl, andperhydrophenanthrenyl.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative —(C₅-C₁₀)cycloalkenyls includecyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl,cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl,cyclononadienyl, cyclodecenyl, and cyclodecadienyl.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative —(C₅-C₈)cycloalkenyls includecyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl,cyclooctadienyl, cyclooctatrienyl, and cyclooctatetraenyl.

“—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls includeindenyl, pentalenyl, naphthalenyl, azulenyl, heptalenyl, and1,2,7,8-tetrahydronaphthalenyl.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls includeanthracenyl, phenanthrenyl, phenalenyl, acenaphthalenyl, as-indacenyl,and s-indacenyl.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, a 5-membered heterocyclecan contain up to 4 heteroatoms, a 6-membered heterocycle can contain upto 6 heteroatoms, and a 7-membered heterocycle can contain up to 7heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 7-membered)heterocycle can be attached via anitrogen or carbon atom. Representative -(3- to 7-membered)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrimidinyl, triazinyl, morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, and tetrahydrothiopyranyl.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, and a 5-memberedheterocycle can contain up to 4 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(3- to5-membered)heterocycle can be attached via a nitrogen or carbon atom.Representative -(3- to 5-membered)heterocycles include furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, andtetrahydrothiophenyl.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone.

The -(7- to 10-membered)bicycloheterocycle can be attached via anitrogen or carbon atom. Representative -(7- to10-membered)bicycloheterocycles include quinolinyl, isoquinolinyl,chromonyl, coumarinyl, indolyl, indolizinyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, carbazolyl, and β-carbolinyl.

“—(C₁₋₄)aryl” means a 14-membered aromatic carbocyclic moiety such asanthryl or phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members where at least one carbon atom is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, the -(5- or 6-membered)heteroaryl's ring contains atleast one carbon atom. Representative -(5- or 6-membered)heteroarylsinclude pyridyl, furyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“Benzyl” means (methyl)benzene, i.e.:

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBrCl, —CHClI, and —CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, —Cl₃, —CClF₂, —CFCl₂, —CClBr₂,—CBrCl₂, and —CFClBr.

“Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“—(C₁-C₈)alkanone” means a keto group in which carbon atoms are in alinear, branched or cyclic alkyl arrangement and, not including the ketocarbon atom, having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.Representative —(C₁-C₈)alkanone groups include acetyl, propionyl,isobutyryl, 2,3-dimethylbutanoyl, 2,3-dimethylheptanoyl,6,6-dimethylheptanoyl, heptan-4-one, pentan-2-one, and5-(4-isopropylhexan-2-one).

“—(C₂-C₈)alkanone” means a keto group in which carbon atoms are in alinear, branched or cyclic alkyl arrangement and, not including the ketocarbon atom, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Representative—(C₂-C₈)alkanone groups include propionyl, isobutyryl,2,3-dimethylbutanoyl, 2,3-dimethylheptanoyl, 6,6-dimethylheptanoyl,heptan-4-one, pentan-2-one, and 5-(4-isopropylhexan-2-one).

“—(C₁-C₈)alkanoyl” means an acyl group in a linear, branched or cyclicarrangement (e.g., —C(═O)-alkyl) and, not including the carbonyl carbonatom, having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Representative—(C₁-C₈)alkanoyl groups include acetyl, propionyl, isobutyryl,2,3-dimethylbutanoyl, 2,3-dimethylheptanoyl, 6,6-dimethylheptanoyl,2-cyclopentylacetyl, 2-(3-methylcyclopentyl)propanoyl,cyclohexanecarbonyl, and 4,4-dimethylcyclohexanecarbonyl.

“—(C₁-C₆)alkanoyl” means an acyl group in a linear, branched or cyclicarrangement (e.g., —C(═O)-alkyl) and, not including the carbonyl carbonatom, having 1, 2, 3, 4, 5, or 6 carbon atoms. Representative—(C₁-C₆)alkanoyl groups include acetyl, propionyl, isobutyryl,2,3-dimethylbutanoyl, 2,3,3-trimethylbutanoyl, 2-cyclopentylacetyl, andcyclohexanecarbonyl.

“—(C₁)alkanoyl” refers to acetyl, i.e., —C(═O)CH₃.

“—(C₁-C₈)alkoxycarbonyl” means an alkoxy group linked via the carbonylcarbon atom of an ester (e.g., a group having the exemplary structure—C(═O)—O-alkyl) and, not including the ester carbon atom, having 1, 2,3, 4, 5, 6, 7, or 8 carbon atoms. Representative —(C₁-C₈)alkoxycarbonylgroups include methyl carboxylate, ethyl carboxylate, propylcarboxylate, isopropyl carboxylate, butyl carboxylate, sec-butylcarboxylate, tert-butyl carboxylate, pentyl carboxylate, tent-pentylcarboxylate, hexyl carboxylate, 3-methylpentan-3-yl carboxylate, heptylcarboxylate, octyl carboxylate, 2,4-dimethylhexan-3-yl carboxylate, and2,3,4-trimethylpentan-3-yl carboxylate.

“—(C₁-C₆)alkoxycarbonyl” means an alkoxy group linked via the carbonylcarbon atom of an ester (e.g., a group having the exemplary structure—C(═O)—O-alkyl) and, not including the ester carbon atom, having 1, 2,3, 4, 5, or 6 carbon atoms. Representative —(C₁-C₈)alkoxycarbonyl groupsinclude methyl carboxylate, ethyl carboxylate, propyl carboxylate,isopropyl carboxylate, butyl carboxylate, sec-butyl carboxylate,tert-butyl carboxylate, pentyl carboxylate, tert-pentyl carboxylate,hexyl carboxylate, and 3-methylpentan-3-ylcarboxylate.

“—(C₁-C₈)alkanoyloxy” means an alkanoyl group linked via the oxygen atomof an ester (e.g., a group having the exemplary structure—O—C(═O)-alkyl) and, not including the ester carbon atom, having 1, 2,3, 4, 5, 6, 7, or 8 carbon atoms. Representative —(C₁-C₈)alkanoyloxygroups include acetate, propionate, butyrate, 2-ethylbutanoate,2,2-diethylbutanoate, pentanoate, 2-ethylpentanoate,2,3-dimethylpentanoate, 3-ethyl-2,4-dimethylpentanoate, hexanoate,5-methylhexanoate, heptanoate, 2,3-dimethylheptanoate, octanoate,nonanoate, and pivalate.

“—(C₁-C₆)alkanoyloxy” means an alkanoyl group linked via the oxygen atomof an ester (e.g., a group having the exemplary structure—O—C(═O)-alkyl) and, not including the ester carbon atom, having 1, 2,3, 4, 5, or 6 carbon atoms. Representative —(C₁-C₆)alkanoyloxy groupsinclude acetate, propionate, butyrate, 2-ethylbutanoate, pentanoate,2-ethylpentanoate, 2,3-dimethylpentanoate, hexanoate, 5-methylhexanoate,heptanoate, and pivalate.

“Phenoxy” means a phenyl group linked via an oxygen atom, i.e., a grouphaving the structure —O-phenyl.

“—(C₁-C₈)alkylthio” means a straight chain or branched optionallyunsaturated non cyclic hydrocarbon having one or more thioether orsulfane groups and from 1 to 8 carbon atoms. Representative straightchain and branched —(C₁-C₈)alkylthio groups include methylsulfane,ethylsulfane, propylsulfane, butylsulfane, pentylsulfane, hexylsulfane,octylsulfane, methyl(methyl)sulfane, ethynyl(methyl)sulfane,5-pentyl(methyl)sulfane, and ethyl(4-butan-2-yl)sulfane.

In connection with the Ar₂ group:

when E is —NH(C₁-C₆)alkyl it is to be understood that the dashed line inthe above Ar₂ group is absent, i.e., the Ar₂ group is:

where Y₁, Y₂, Y₃, R₁₄, c and t are as defined above for compounds offormulae I-III. When E is ═O, ═S, ═CH(C₁-C₆)alkyl, ═CH(C₂-C₆)alkenyl, or═N—OR₂₀, it is to be understood that the dashed line in the above Ar₂group is present, i.e., the Ar₂ group is:

respectively, where Y₁, Y₂, Y₃, R₁₄, R₂₀, c and t are as defined abovefor compounds of formulae I-III.

The term “pyridyl group” means:

where R₁, R₂, and n are as defined above for compounds of formulaeI-III, and where the numbers designate the position of each atom in thering.

The term “pyrazinyl group” means:

where R₁, R₂, and p are as defined above for compounds of formulaeI-III.

The term “pyrimidinyl group” means:

where R₁, R₂, and p are as defined above for compounds of formulaeI-III.

The term “pyridazinyl group” means:

where R₁, R₂, and p are as defined above for compounds of formulaeI-III.

The term “5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine ring” means:

The term “benzoimidazolyl group” means:

where R₈, R₉, and R₂₀ are as defined above for compounds of formulaeI-III.

The term “benzothiazolyl group” means:

where R₈ and R₉ are as defined above for compounds of formulae I-III.

The term “benzooxazolyl group” means:

where R₈ and R₉ are as defined above for compounds of formulae I-III.

In connection with the Ar₂ group, the term “phenyl” group means:

where R₁₄ and s are as defined for compounds of formulae I-III.

In connection with the group of formula -M-A-R₂₄, the term “pyrrolidine”means:

where g is the integer 1, 2 or 3.

In connection with the group of formula -M-A-R₂₄, the term “piperidine”means:

where g is the integer 1, 2 or 3.

In connection with the group of formula -M-A-R₂₄, the term “piperazine”means:

where g is the integer 1, 2 or 3.

In connection with the group of formula -M-A-R₂₄, the term “morpholine”means:

where g is the integer 1, 2 or 3.

The term “animal,” includes, but is not limited to, a cow, monkey,baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig, and human.

The term “pharmaceutically acceptable derivative,” as used herein,includes any pharmaceutically acceptable salt, solvate, radiolabeled,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of a compoundof formulae I-III of the invention. In one embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, solvate, radiolabeled, stereoisomer, enantiomer, diastereomer,other stereoisomeric form, racemic mixture, geometric isomer, and/ortautomer, e.g., of a compound of formulae I-III of the invention. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, e.g., of a compound of formulae I(a),I(b), I(c), or I(d), of the invention.

The term “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from a compound offormulae I-III, including a salt formed from an acid and a basicfunctional group, such as a nitrogen group, of one of the compounds offormulae I-III. Illustrative salts include, but are not limited, tosulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a compound of formulae I-III having an acidic functionalgroup, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine and thelike. One in the art will recognize that, e.g., acid addition salts of acompound of formulae I-III can be prepared by reaction of the compoundswith the appropriate acid via a variety of known methods.

Compounds of formulae I-III encompass all solvates of compounds offormulae I-III. “Solvates” are known in the art and are considered to bea combination, physical association and/or solvation of a compound offormulae I-III with a solvent molecule, e.g., a disolvate, monosolvateor hemisolvate when the ratio of the solvent molecule to the molecule ofthe compound of formula I is 2:1, 1:1 or 1:2, respectively. Thisphysical association involves varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances, the solvatecan be isolated, for example when one or more solvent molecules areincorporated into the crystal lattice of a crystalline solid. Thus,“solvate,” as used herein, encompasses both solution-phase andisolatable solvates. A compound of formulae I-III of the invention canbe present as a solvated form with a pharmaceutically acceptablesolvent, such as water, methanol, ethanol, and the like, and it isintended that the invention include both solvated and unsolvatedcompound of formula I forms. As “hydrate” relates to a particularsubgroup of solvates, i.e., where the solvent molecule is water,hydrates are included within the solvates of the invention. Preparationof solvates is known in the art. For example, M. Caira et al., J.Pharmaceut. Sci., 93(3):601-611 (2004), describes the preparation ofsolvates of fluconazole with ethyl acetate and with water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1),article 12 (2004), and A. L. Bingham et al., Chem. Commun., 603-604(2001). A typical, non-limiting, process involves dissolving thecompound of formula I in a desired amount of the desired solvent(organic, water or mixtures thereof) at temperatures above about 20° C.to about 25° C., cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques, for example, infrared spectroscopy, can be usedto show the presence of the solvent in a crystal of the solvate.

The invention disclosed herein is also meant to encompass all prodrugsof the compounds of the invention. “Prodrugs” are known in the art and,while not necessarily possessing any pharmaceutical activity as such,are considered to be any covalently bonded carrier(s) that releases theactive parent drug in vivo. In general, such prodrugs will be afunctional derivative of a compound of formulae I-III which is readilyconvertible in vivo, e.g., by being metabolized, into the requiredcompound of formulae I-III. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described in, forexample, Design of Prodrugs, H. Bundgaard, Ed., Elsevier (1985); “Drugand Enzyme Targeting, Part A,” K. Widder et al., Eds., Vol. 112 inMethods in Enzymology, Academic Press (1985); Bundgaard, “Design andApplication of Prodrugs,” Chapter 5 (pp. 113-191) in A Textbook of DrugDesign and Development, P. Krogsgaard-Larsen and H. Bundgaard, Eds.,Harwood Academic Publishers (1991); Bundgaard et al., Adv. Drug DeliveryRevs. 8:1-38 (1992); Bundgaard et al., J. Pharmaceut. Sci. 77:285(1988); and Kakeya et al., Chem. Pharm. Bull. 32:692 (1984).

Examples of prodrugs include esters or amides of formulae I-III with anyof R₂-R₈ as hydroxyalkyl or aminoalkyl, and these can be prepared byreacting such compounds with anhydrides such as succinic anhydride.

In addition, one or more hydrogen, carbon or other atoms of a compoundof formulae I-III can be replaced by an isotope of the hydrogen, carbonor other atoms. Compounds of formulae I-III include all radiolabeledforms of compounds of formulae I-III. Such a “radiolabeled,”“radiolabeled form”, and the like of a compound of formulae I-III, eachof which is encompassed by the invention, is useful as a research and/ordiagnostic tool in metabolism pharmacokinetic studies and in bindingassays. Examples of isotopes that can be incorporated into a compound offormulae I-III of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Radiolabeled compounds of the invention can be prepared bymethods known in the art. For example, tritiated compounds of formulaeI-III can be prepared by introducing tritium into the particularcompound of formulae I-III, for example, by catalytic dehalogenationwith tritium. This method can include reacting a suitablyhalogen-substituted precursor of a compound of formulae I-III withtritium gas in the presence of a suitable catalyst, for example, Pd/C,in the presence or absence of a base. Other suitable methods forpreparing tritiated compounds can be found in Filer, Isotopes in thePhysical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A),Chapter 6 (1987). ¹⁴C-labeled compounds can be prepared by employingstarting materials having a ¹⁴C carbon.

A compound of formulae I-III can contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Compounds of formulae I-III encompass all suchpossible forms as well as their racemic and resolved forms or anymixture thereof. When a compound of formulae I-III contains an olefinicdouble bond or other center of geometric asymmetry, and unless specifiedotherwise, it is intended to include all “geometric isomers,” e.g., bothE and Z geometric isomers. All “tautomers,” e.g., ketone-enol,amide-imidic acid, lactam-lactim, enamine-imine, amine-imine, andenamine-enimine tautomers, are intended to be encompassed by theinvention as well.

As used herein, the terms “stereoisomer,” “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

Stereoisomers, e.g., optical isomers, of a compound of formulae I-IIIcan be obtained by known techniques such as chiral chromatography orformation of diastereomeric salts from an optically active acid or base.

Stereoisomeric, e.g., optical, purity can be stated in terms ofenantiomeric excess (% ee), which is determined by the formula:

${\%\mspace{14mu}{ee}} = {\left\lbrack \frac{{{major}{\mspace{11mu}\;}{enantiomer}\mspace{14mu}({mol})} - {{minor}{\mspace{11mu}\;}{enantiomer}\mspace{14mu}({mol})}}{{{major}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})} + {{minor}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})}} \right\rbrack \times 100.}$

The term “effective amount,” when used in connection with a compound offormulae I-III means an amount effective for: (a) treating or preventinga Condition; or (b) inhibiting TRPV1 function in a cell.

The term “effective amount,” when used in connection with a secondtherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

The term “therapeutic index,” describes the gap between the dose that iseffective, and the dose that induces adverse effects.

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, the number of second groups is one or two. In anotherembodiment, the number of second groups is one.

The term “EtOH” means ethanol, i.e., ethyl alcohol.

The term “t-BuOH” means tert-butyl alcohol, i.e., 2-methylpropan-2-ol.

The term “THF” means tetrahydrofuran.

The term “DMF” means N,N-dimethylformamide.

The term “NH₄OH” means ammonium hydroxide.

The term “TEA” means triethylamine.

The terms “MeCN” and “CH₃CN” mean acetonitrile.

The term “DMSO” means dimethylsulfoxide, i.e., methylsulfinylmethane.

The term “BOC” means tert-butyloxycarbonyl:

The term “TsOH” means p-toluenesulfonic acid or toluene-4-sulfonic acid.

The term “OTf” means trifluoromethanesulfonate or triflate.

The term “Pd(PPh₃)₄” means tetrakis(triphenylphosphine)palladium.

The term “PPh₃CH₃Br” means methyltriphenylphosphonium bromide.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The terms “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasingthe overall frequency of episodes of a Condition or a symptom thereof.

The terms “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof.

4.5. METHODS FOR MAKING COMPOUNDS OF FORMULAE I-III

The compounds of the invention can be prepared from readily availablestarting materials using conventional organic synthesis methods andprocedures known in the art and/or by the illustrative methods shown inthe schemes below. Optimum reaction conditions can vary with theparticular reactants or solvents used and such conditions can bedetermined by one in the art by routine optimization procedures. Ifdesired, the product(s) can be isolated and purified by known standardprocedures. Such procedures include, but are not limited to,recrystallization, column chromatography, thin-layer chromatography(“TLC”), preparative TLC, high pressure liquid chromatography (“HPLC”)and/or preparative HPLC. If a single stereoisomer is desired, it ispossible to use chiral separation techniques known in the art, such aschiral chromatography or chiral resolution, to isolate a single isomeror to use enantiomerically pure or enriched starting materials orenantioselective methods of synthesis.

Additionally, as will be apparent to those in the art, conventionalprotecting groups can be used to prevent certain functional groups fromundergoing undesired reactions. The choice of a suitable protectinggroup(s) for a particular functional group as well as suitableconditions for protection and deprotection are known in the art. Forexample, numerous protecting groups and their introduction and removalare described in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, 2^(nd) Edition, Wiley, New York, 1991, and thereferences cited therein.

Procedures for obtaining compounds of the invention can be derived byappropriately modifying in view of the present disclosure the methodsdisclosed in, for example, U.S. Patent Application Publication Nos. US2005/0165032 A1, US 2004/0156869 A1 and US 2006/0229307 A1, the entiredisclosure of each of which is incorporated herein by reference in itsentirety. In addition, U.S. Patent Application Publication No. US2009/0170868 A1, the entire disclosure of which is incorporated hereinby reference in its entirety, describes the synthesis of variousQ-groups of the invention.

In the following schemes, the Ar₁ group is typically depicted ascomprising 2-pyridyl for illustrative purposes only. However, any otherAr₁ group as described in the invention can also be used. In thefollowing schemes, the Q group is typically depicted as1,2-dihydroxyethyl for illustrative purposes only. However, any other Qgroup as described in the invention can also be used. The exemplary1,2-dihydroxyethyl group may be shown with only one stereochemicalconfiguration. However any configuration selected from (S), (R), or amixture thereof is possible. Methods for stereoselective synthesis aredescribed in the examples below.

In the following Schemes, the term “hydrolyze” refers to the reaction ofwater with a nitrile or ester moiety resulting in the formation of anamide or a carboxylic acid moiety, respectively. This reaction can beaided by the addition of a number of acidic or basic catalysts known tothose in the art.

In the following Schemes, “reduce” refers to the process of reducing anitro functionality to an amino functionality. This reaction can becarried out in a number of ways known to those in the art including, butnot limited to, catalytic hydrogenation, reduction with SnCl₂, andreduction with titanium trichloride. For an overview of reductionmethods see: M. Hudlicky, Reductions in Organic Chemistry, ACS Monograph188 (1996).

In the following Schemes, the term “activate” refers to the reactionwhere a carbonyl of an amide moiety is converted to a suitable leavinggroup. Reagents suitable for carrying out this reaction are known tothose in the art and include, but are not limited to, SOCl₂, POCl₃, andtriflic anhydride (“TFA”).

4.5.1. Methods for Making Compounds of Formulae I(a), I(b), and I(c)

Compounds of formulae I(a), I(aa), II(a), II(aa), III(ab) and others canbe made by the synthetic method shown in Scheme 1 or 2.

Compounds of formulae I(a), I(aa), I(ac), II(a), II(aa), III(a),III(ab), III(cb) and others can be made by the synthetic method shown inScheme 3.

It should be noted that the method described in Scheme 3 is suitable forpreparing compounds of the invention where the R₃ group is attached tothe bicyclic ring system via a CH₂ moiety, which CH₂ moiety is part ofthe R₃ group.

Compounds of formulae I(a), I(ad), II(a), II(ad), III(d), III(db) andothers can be made by the synthetic method shown in Scheme 4. Althoughspecific R₃ groups are exemplified in Scheme 4, reagents suitable fortransforming these groups into other R₃ groups described herein, e.g.,see Step 4, are known to those in the art.

Compounds of formulae I(a), I(ae), II(ae), III(e), III(eb) and otherscan be made by the synthetic method shown in Scheme 5.

Compounds of formulae I(c), I(cb), II(c), II(cb), III(l), III(lb) andothers can be made by the synthetic method shown in Scheme 6.

Compounds of formulae I(a), I(ag), II(ag), III(h), III(hb) and otherscan be made by the synthetic method shown in Scheme 7. Although specificR₃ groups are exemplified in Scheme 7, reagents suitable fortransforming these groups into other R₃ groups described herein, e.g.,see Step 2, are known to those in the art.

Compounds of formulae I(b), I(ba), II(b), II(ba), III(i), III(ib) andothers can be made by the synthetic method shown in Schemes 8 or 9.Methods for preparing compound S8A are known to those in the art.

Protecting groups are removed under conditions which do not target theremaining portion of the molecule. These methods are known in the artand include acid hydrolysis, hydrogenolysis, and the like. A preferredmethod involves removal of a protecting group, such as abenzyloxycarbonyl group, by hydrogenolysis utilizing palladium on carbonin a suitable solvent system such as an alcohol, acetic acid, and thelike or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved by an inorganic or organic acid, such as HCl or trifluoroaceticacid, in a suitable solvent system, such as dioxane or methylenechloride. The resulting amino salt can readily be neutralized to yieldthe free amine. A carboxy protecting group, such as methyl, ethyl,benzyl, tert-butyl, 4-methoxyphenylmethyl, and the like, can be removedunder hydrolysis and hydrogenolysis conditions known to those in theart.

Compound S8a can be reacted with H—X—Ar₂ to provide compound S9A. Ifnecessary, the reaction can be carried out in the presence of a baseand/or heat. The protecting group P can be removed by methods known tothose in the art. In a subsequent reaction step, the Ar₁ group can beattached to compound S9B to provide compound S9C.

4.5.2. Methods for Attaching an R₂ Group to Ar₁ when R₂ is Q

It can sometimes be advantageous to attach a Q-group to the Ar₁ group ina separate reaction step after the core molecule has been built up. Asan example, the formation of a 1,2-dihydroxyethyl group on a 2-pyridylsubstituent as the Ar₁ group is described, below. However, this exampleis provided for illustrative purposes only and shall not be construed tolimit the scope of the invention.

The conversion of a halide (L) to a vinyl group by a Suzukicross-coupling reaction is described in Scheme 10 below. While in Scheme10 the conversion is illustrated for Ar₁ groups when L is in the5-position of the pyridyl ring of compound S10A, the reaction can alsobe carried out when L is in other positions on any of the other Ar₁ arylor heteroaryl ring as well. Thus, the same technique can be used whenAr₁ comprises a phenyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

In Scheme 10 where L is Cl, Br or I, compound S10A can be reacted with adi-n-butyl boronic ester in the presence of palladium diphenylphosphinoferrocene dichloride (Pd(DPPF)₂Cl₂, also known as1,1′-bis(diphenylphosphino)ferrocene-palladium(H)dichloride) and CsF ina suitable solvent. The reaction mixture can then be reacted at elevatedtemperatures for a suitable time period and the expected product can beseparated by conventional methods known to one in the art, such ascolumn chromatography, to provide compound S10B.

Other suitable techniques for attaching a vinyl group are shown inSchemes 11 and 12. In Scheme 11, the first step can involve theoxidation of a benzylic alcohol to the corresponding aldehyde. This canbe followed by a Wittig olefination to yield the vinyl group. Onceagain, while the starting benzylic alcohol illustrated is substituted inthe 5-position of a pyridyl ring, similar reactions can be carried outwhen that alcohol is substituted at other positions of the aryl orheteroaryl ring. Moreover, the same technique can be used when Ar₁comprises a phenyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

Manganese oxide can be added to a solution of compound S11A in asuitable solvent such as CH₂Cl₂. The resulting mixture can be stirred ata temperature of about 25° C. Product compound S11B can be separated byfiltration and subsequent column chromatography.

To a cooled slurry of methyltriphenylphosphonium bromide in a suitablesolvent such as toluene, potassium t-butoxide can be added. Afterstirring for 1-5 h at a temperature of about 25° C., the reactionmixture can be cooled to about −20° C. Thereafter, compound S11Bdissolved in tetrahydrofuran can be added dropwise to the slurry. Thereaction mixture is allowed to warm to about 0° C. and stirred foradditional 1 hr. The resulting product can be worked up followingstandard procedures and can optionally be purified by columnchromatography to provide compound S10B.

In Scheme 12, the first reaction step involves the reduction of abenzylic ketone to a hydroxyl. This can be followed by a dehydrationreaction to yield a vinyl group.

Once again, while in Scheme 12 the starting benzylic ketone illustratedis substituted in the 5-position of a pyridyl ring, similar reactionscan be carried out when the substitution is at other positions of thearyl or heteroaryl ring. Moreover, the same technique can be used whenAr₁ comprises a phenyl, pyrimidinyl, pyrazinyl or pyridazinyl ring.

To a suspension of compound S12A at 0° C. in a suitable solvent, such asmethanol, sodium borohydride can be added portionwise at a rate suchthat the reaction mixture temperature does not exceed 5° C.Subsequently, the reaction mixture can be stirred an additional 1 h at atemperature of about 25° C. The reaction mixture can be worked upfollowing standard procedures, such as extraction and optionallypurification by column chromatography, to provide compound S12B.

To a solution of compound S12B in a suitable solvent such aschlorobenzene can be added p-toluene sulfonic acid. The reaction mixturecan be heated to reflux and water can be removed concurrently. At thecompletion of the reaction, the mixture is concentrated and extractedfollowing standard procedures. Optionally, product compound S10B canthen be purified, e.g., by column chromatography.

Vinyl groups are highly versatile, because they are a synthetic “handle”that can be further modified. For example, it is known in syntheticorganic chemistry that olefin hydrolysis provides a benzylic hydroxylgroup, hydroboration gives a primary hydroxyl group, ozonolysis gives analdehyde or ketone, oxidation gives a carboxylic acid, olefin metathesisextends the chain, and dihydroxylation gives a 1,2-diol. Many additionalolefin functionalization techniques are known to those in the art. Oncefunctionalized, the group can undergo further reaction(s). In Scheme 13an asymmetric dihydroxylation of the vinyl group is described.

A vinyl compound, e.g., the exemplary but non-limiting pyridyl compoundS10B, can be reacted with AD-mix α (alpha) to provide compound S13A. Asdescribed in Scheme 13, the stereochemistry (R or S) of the resultingdiol is dependent upon the chirality of the ligand used in the AD mix asdescribed in Sharpless et al., J. Org. Chem. 57:2768-2771 (1992). AD-mixis composed of the following components: potassium osmate (K₂OsO₂(OH)₄),potassium ferricyanide (K₃Fe(CN)₆), potassium carbonate (K₂CO₃), and thechiral ligands shown in Scheme 14. The reaction of vinyl compounds withAD-mix is described in, e.g., U.S. Patent Application Publication No. US2009/0170868 A1.

The other enantiomer S13B can be synthesized by the reaction of thevinyl compound S10B and AD-mix β (beta).

The racemic diol, compound S13C, can be synthesized by methods known inthe art, e.g., reacting with osmium tetroxide (OsO₄) and N-methylmorpholine N-oxide (NMO) in an aqueous acetone solution.

4.6. THERAPEUTIC USES OF COMPOUNDS OF FORMULAE I-III

In accordance with the invention, the compounds of formulae I-III areadministered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a compound of formulae I-IIIcan be used to treat or prevent any condition treatable or preventableby inhibiting TRPV1. Examples of Conditions that are treatable orpreventable by inhibiting TRPV1 include, but are not limited to, pain,UI, an ulcer, IBD, and IBS.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent acute or chronicpain. Examples of pain treatable or preventable using the compounds offormulae I-III include, but are not limited to, cancer pain, labor pain,myocardial infarction pain, pancreatic pain, colic pain, post-operativepain, headache pain, muscle pain, arthritic pain, and pain associatedwith a periodontal disease, including gingivitis and periodontitis.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can also be used for treating or preventing painassociated with inflammation or with an inflammatory disease in ananimal. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response and/or a systemicinflammation. For example, the compounds of formulae I-III can be usedto treat or prevent pain associated with inflammatory diseasesincluding, but not limited to: organ transplant rejection; reoxygenationinjury resulting from organ transplantation (see Grupp et al., J. Mol.Cell. Cardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory diseases of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory diseases of the skin, includingsclerodermatitis, psoriasis and eczema; inflammatory diseases of thecentral nervous system, including chronic demyelinating diseases of thenervous system, multiple sclerosis, AIDS-related neurodegeneration andAlzheimer's disease, infectious meningitis, encephalomyelitis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosisand viral or autoimmune encephalitis; autoimmune diseases, includingType I and Type II diabetes mellitus; diabetic complications, including,but not limited to, diabetic cataract, glaucoma, retinopathy,nephropathy (such as microalbuminuria and progressive diabeticnephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy,gangrene of the feet, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma,foot ulcers, joint problems, and a skin or mucous membrane complication(such as an infection, a shin spot, a candidal infection or necrobiosislipoidica diabeticorum); immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory diseases of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. The compoundsof formulae can also be used for inhibiting, treating, or preventingpain associated with inflammatory disease that can, for example, be asystemic inflammation of the body, exemplified by gram-positive or gramnegative shock, hemorrhagic or anaphylactic shock, or shock induced bycancer chemotherapy in response to pro-inflammatory cytokines, e.g.,shock associated with pro-inflammatory cytokines. Such shock can beinduced, e.g., by a chemotherapeutic agent that is administered as atreatment for cancer.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent UI. Examples of UItreatable or preventable using the compounds of formulae I-III include,but are not limited to, urge incontinence, stress incontinence, overflowincontinence, neurogenic incontinence, and total incontinence.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent an ulcer. Examplesof ulcers treatable or preventable using the compounds of formulae I-IIIinclude, but are not limited to, a duodenal ulcer, a gastric ulcer, amarginal ulcer, an esophageal ulcer, or a stress ulcer.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent IBD, includingCrohn's disease and ulcerative colitis.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent IBS. Examples of IBStreatable or preventable using the compounds of formulae I-III include,but are not limited to, spastic-colon-type IBS andconstipation-predominant MS.

Applicants believe that the compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, are antagonists forTRPV1.

The invention also relates to methods for inhibiting TRPV1 function in acell comprising contacting a cell capable of expressing TRPV1 with aneffective amount of a compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof. This method can be used in vitro, forexample, as an assay to select cells that express TRPV1 and,accordingly, are useful as part of an assay to select compounds usefulfor treating or preventing pain, UI, an ulcer, IBD, or IBS. In anotherembodiment, the invention relates to an in vitro method for inhibitingTRPV1 function in a cell comprising contacting a cell expressing TRPV1in vitro with a compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof, in an amount sufficient to reduce calciumion mobilization into a cell treated with an activator of TRPV1 ascompared to a cell expressing TRPV1 in vitro treated with an activatorof TRPV1 and not contacted with the compound. In another embodiment, thecalcium ion mobilization is reduced by 50% or more.

The method is also useful for inhibiting TRPV1 function in a cell invivo, in an animal, a human in one embodiment, by contacting a cell, inan animal, with an effective amount of a compound of formulae I-III, ora pharmaceutically acceptable derivative thereof. In another embodiment,the invention relates to an in vivo method for inhibiting TRPV1 functionin a cell comprising contacting a cell expressing TRPV1 in vivo with acompound of formulae I-III, or a pharmaceutically acceptable derivativethereof, where the compound is capable, in an in vitro assay, ofreducing calcium ion mobilization into a cell expressing TRPV1 andtreated with an activator of TRPV1 by 50% or more as compared to a cellexpressing TRPV1 treated with an activator of TRPV1 and not contactedwith the compound. In another embodiment, the invention relates to an invivo method for inhibiting TRPV1 function in a cell comprisingcontacting a cell expressing TRPV1 in vivo with a compound of formulaeI-III, or a pharmaceutically acceptable derivative thereof, where thecompound is capable of reducing pain as or more effectively than asimilar dose of one or more of the positive control analgesicscelecoxib, indomethacin or naproxen, as measured by one or more of thein vivo pain tests consisting of an acute pain test, an inflammatorypain test, a neuropathic pain test, a mechanical stimuli pain test, athermal stimuli pain test, or a tactile allodynia test.

In another embodiment, the method is useful for treating or preventingpain in an animal. In another embodiment, the invention relates to amethod of treating pain in an animal, comprising administering to ananimal in need of treatment for pain a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, in an amount from 0.01mg/kg body weight to 2500 mg/kg body weight where the compound iscapable of reducing pain as or more effectively than a similar dose ofone or more of the positive control analgesics celecoxib, indomethacin,or naproxen, as measured by one or more of the in vivo pain testsconsisting of an acute pain test, an inflammatory pain test, aneuropathic pain test, a mechanical stimuli pain test, a thermal stimulipain test, or a tactile allodynia test. In another embodiment, themethod is useful for treating or preventing UI in an animal. In anotherembodiment, the method is useful for treating or preventing an ulcer inan animal. In another embodiment, the method is useful for treating orpreventing IBD in an animal. In another embodiment, the method is usefulfor treating or preventing IBS in an animal.

Examples of tissue comprising cells capable of expressing TRPV1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express TRPV1 are known in theart.

4.7. THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THEINVENTION

Due to their activity, compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, are advantageouslyuseful in veterinary and human medicine. As described above, compoundsof formulae I-III or a pharmaceutically acceptable derivative thereof,are useful for treating or preventing a Condition.

When administered to an animal, compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, are typicallyadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The compositions ofthe invention, which comprise a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, can be administeredorally. Compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can also be administered by any other convenientroute, for example, by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral, rectal, andintestinal mucosa, etc.) and can be administered together with a secondtherapeutically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister the compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, into the bloodstream.

In specific embodiments, it can be desirable to administer the compoundsof formulae I-III, or a pharmaceutically acceptable derivative thereof,locally. This can be achieved, for example, and not by way oflimitation, by local infusion during surgery, topical application, e.g.,in conjunction with a wound dressing after surgery, by injection, bymeans of a catheter, by means of a suppository or enema, or by means ofan implant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the compoundsof formulae I-III, or a pharmaceutically acceptable derivative thereof,into the central nervous system or gastrointestinal tract by anysuitable route, including intraventricular, intrathecal, and epiduralinjection, and enema. Intraventricular injection can be facilitated byan intraventricular catheter, for example, attached to a reservoir, suchas an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of formulae I-III can be formulatedas a suppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990) and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, can be delivered in acontrolled-release system or sustained-release system (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled- or sustained-release systemsdiscussed in the review by Langer, Science 249:1527-1533 (1990) can beused. In one embodiment, a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987);Buchwald et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J.Med. 321:574 (1989)). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release (Langer and Wise,Eds., 1974); Controlled Drug Bioavailability, Drug Product Design andPerformance (Smolen and Ball, Eds., 1984); Langer and Peppas, J.Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy et al., Science228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); and Howard etal., J. Neurosurg. 71:105 (1989)). In yet another embodiment, acontrolled- or sustained-release system can be placed in proximity of atarget of the compounds of formulae I-III, e.g., the spinal column,brain, or gastrointestinal tract, thus requiring only a fraction of thesystemic dose.

The compositions of the invention can optionally comprise a suitableamount of a pharmaceutically acceptable excipient so as to provide theform for proper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to an animal. Water is a particularlyuseful excipient when the compound of formulae I-III is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The compositions of the invention, if desired, can alsocontain minor amounts of wetting or emulsifying agents, or can containpH buffering agents.

The compositions of the invention can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, multiparticulates,capsules, capsules containing liquids, powders, multiparticulates,sustained-release formulations, suppositories, emulsions, aerosols,sprays, suspensions, or any other form suitable for use. In oneembodiment, the composition is in the form of a capsule (see e.g., U.S.Pat. No. 5,698,155). Other examples of suitable pharmaceuticalexcipients are described in Remington's Pharmaceutical Sciences1447-1676 (A. R. Gennaro, Ed., 19th Ed. 1995), incorporated herein byreference.

In one embodiment, the compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, powdered or microcrystalline cellulose,cellulose derivatives, dibasic calcium hydrogen phosphate, colloidalsilicon dioxide, magnesium carbonate, and other substances known fromthe pharmaceutical literature such as further lubricants, glidants,colorants, surfactants or flavors. In one embodiment, the excipients areof pharmaceutical grade.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be administered by controlled-release orsustained-release means or by delivery devices that are known to thoseof ordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose,ethylcellulose, other polymer matrices, gels, permeable membranes,osmotic systems, multilayer coatings, microparticles, liposomes,microspheres, or a combination thereof to provide the desired releaseprofile in varying proportions. Suitable controlled- orsustained-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a compound of formulae I-III to cure or control the conditionin a minimum amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased patient compliance. In addition,controlled- or sustained-release compositions can favorably affect thetime of onset of action or other characteristics, such as blood levelsof the compound of formulae I-III, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can be designed toimmediately release an amount of a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the compound of formulae I-III tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the compound offormulae I-III in the body, the compound of formulae I-III can bereleased from the dosage form at a rate that will replace the amount ofcompound of formulae I-III being metabolized and excreted from the body.Controlled- or sustained-release of an active ingredient can bestimulated by various conditions, including but not limited to, changesin pH, changes in temperature, concentration or availability of enzymes,concentration or availability of water, or other physiologicalconditions or compounds.

In another embodiment, the compounds of formulae I-III, or apharmaceutically acceptable derivative thereof, can be formulated forintravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lignocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampoule or sachette indicating the quantity of active agent. Wherethe compounds of formulae I-III are to be administered by infusion, theycan be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where the compounds offormulae I-III, or a pharmaceutically acceptable derivative thereof, areadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

The amount of the compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof, that is effective in the treatment orprevention of a Condition can be determined by standard clinicaltechniques. In addition, in vitro or in vivo assays can optionally beemployed to help identify optimal dosage ranges. The precise dose to beemployed will also depend on the route of administration, and theseriousness of the Condition and can be decided according to thejudgment of a practitioner and/or each animal's circumstances. Suitableeffective dosage amounts, however, will typically range from about 0.01mg/kg of body weight to about 2500 mg/kg of body weight, although theyare typically about 100 mg/kg of body weight or less. In one embodiment,the effective dosage amount ranges from about 0.01 mg/kg of body weightto about 100 mg/kg of body weight of a compound of formulae I-III; inanother embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg ofbody weight; and in another embodiment, about 0.025 mg/kg of body weightto about 20 mg/kg of body weight.

In one embodiment, an effective dosage amount is administered aboutevery 24 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 12 h until theCondition is abated. In another embodiment, an effective dosage amountis administered about every 8 h until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 h until theCondition is abated.

The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one compound of formulae I-III, or apharmaceutically acceptable derivative thereof, is administered, theeffective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing TRPV1 is contacted with a compound offormulae I-III in vitro, the amount effective for inhibiting the TRPV1receptor function in a cell will typically range from about 0.01 μg/L toabout 5 mg/L; in one embodiment, from about 0.01 μg/L to about 2.5 mg/L;in another embodiment, from about 0.01 μg/L to about 0.5 mg/L; and inanother embodiment, from about 0.01 μg/L to about 0.25 mg/L, of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspensioncomprising the compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof, is from about 0.01 μl, to about 1 mL. Inanother embodiment, the volume of solution or suspension is about 200μL.

The compounds of formulae I-III, or a pharmaceutically acceptablederivative thereof, can be assayed in vitro or in vivo for the desiredtherapeutic or prophylactic activity prior to use in humans. Animalmodel systems can be used to demonstrate safety and efficacy.

The methods for treating or preventing a Condition in an animal in needthereof can further comprise co-administering to the animal beingadministered a compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof (i.e., a first therapeutic agent), asecond therapeutic agent. In one embodiment, the second therapeuticagent is administered in an effective amount.

An effective amount of the second therapeutic agent will be known tothose in the art depending on the agent. However, it is well within theartisan's purview to determine the second therapeutic agent's optimaleffective-amount range. A compound of formulae I-III, or apharmaceutically acceptable derivative thereof, and the secondtherapeutic agent combined can act either additively or synergisticallyto treat the same Condition, or they may act independently of each othersuch that the compound of formulae I-III, or a pharmaceuticallyacceptable derivative thereof, treats or prevents a first Condition andthe second therapeutic agent treats or prevents a second disorder, whichcan be the same as the first Condition or another disorder. In oneembodiment of the invention, where a second therapeutic agent isadministered to an animal for treatment of a Condition (e.g., pain), theminimal effective amount of the compound of formulae I-III, or apharmaceutically acceptable derivative thereof, will be less than itsminimal effective amount would be where the second therapeutic agent isnot administered. In this embodiment, the compound of formulae I-III, ora pharmaceutically acceptable derivative thereof, and the secondtherapeutic agent can act synergistically to treat or prevent aCondition. In one embodiment, a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, is administeredconcurrently with a second therapeutic agent as a single compositioncomprising an effective amount of a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, and an effective amountof the second therapeutic agent. Alternatively, a composition comprisingan effective amount of a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, and a second compositioncomprising an effective amount of the second therapeutic agent areconcurrently administered. In another embodiment, an effective amount ofa compound of formulae I-III, or a pharmaceutically acceptablederivative thereof, is administered prior or subsequent toadministration of an effective amount of the second therapeutic agent.In this embodiment, the compound of formulae I-III, or apharmaceutically acceptable derivative thereof, is administered whilethe second therapeutic agent exerts its therapeutic effect, or thesecond therapeutic agent is administered while the compound of formulaeI-III, or a pharmaceutically acceptable derivative thereof, exerts itstherapeutic effect for treating or preventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroid anti-inflammatory agent,an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca²⁺-channel blocker,an anticancer agent, an agent for treating or preventing UI, an agentfor treating or preventing an ulcer, an agent for treating or preventingIBD, an agent for treating or preventing IBS, an agent for treatingaddictive disorder, an agent for treating Parkinson's disease andparkinsonism, an agent for treating anxiety, an agent for treatingepilepsy, an agent for treating a stroke, an agent for treating aseizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, and mixturesthereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable derivativesthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable derivatives thereof, and mixtures thereof.Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophennol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see P. A. Insel, Analgesic-Antipyretic and Anti-inflammatoryAgents and Drugs Employed in the Treatment of Gout, in Goodman &Gilman's The Pharmacological Basis of Therapeutics 617-57 (P. B.Molinhoff and R. W. Ruddon, Eds., 9^(th) Ed. 1996) and G. R. Hanson,Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: TheScience and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro, Ed.,19th Ed. 1995) which are hereby incorporated by reference in theirentireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

The second therapeutic agent can also be an agent useful for reducingany potential side effects of a compound of formulae I-III. For example,the second therapeutic agent can be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befimolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine;prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsaprione, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlaflaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A composition of the invention is prepared by a method comprisingadmixing a compound of formulae I-III or a pharmaceutically acceptablederivative and a pharmaceutically acceptable carrier or excipient.Admixing can be accomplished using methods known for admixing a compound(or salt) and a pharmaceutically acceptable carrier or excipient. In oneembodiment, the compound of formulae I-III is present in the compositionin an effective amount.

4.8. KITS

The invention further encompasses kits that can simplify the handlingand administration of a compound of formulae I-III, or apharmaceutically acceptable derivative thereof, to an animal.

A typical kit of the invention comprises a unit dosage form of acompound of formulae I-III. In one embodiment, the unit dosage form is acontainer, which can be sterile, containing an effective amount of acompound of formulae I-III and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the compound of formulae I-III to treat aCondition. The kit can further comprise a unit dosage form of a secondtherapeutic agent, for example, a second container containing aneffective amount of the second therapeutic agent and a pharmaceuticallyacceptable carrier or excipient. In another embodiment, the kitcomprises a container containing an effective amount of a compound offormulae I-III, an effective amount of a second therapeutic agent and apharmaceutically acceptable carrier or excipient. Examples of secondtherapeutic agents include, but are not limited to, those listed above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

The following examples illustrate various aspects of the invention, andare not to be construed to limit the claims in any manner whatsoever.

5.1 Example 1 Stereoselective Synthesis of Aromatic, Chiral DiolCompounds

The stereoselective synthesis of aromatic, chiral diol compounds such ascompounds IA and 2A (see Schemes 1 and 2) is important. For thestereoselective synthesis, a vinyl substituted aromatic ring can be usedas intermediate. The aromatic ring can also be heteroaromatic,containing one or more nitrogen atoms.

This approach is illustrated by the synthesis of(S)-1-(5,6-dichloropyridin-3-ylethane-1,2-diol and(R)-1-(5,6-dichloropyridin-3-ylethane-1,2-diol.

To a stirred slurry of AD-mix α (8.95 g) or AD-mix β (8.95 g) in water(32 mL) and tert-butyl alcohol (27 mL) at 0° C. was added a solution of1 (0.909 g, 5.25 mmol) in tert-butyl alcohol (5 mL). After 24 hrs, solidsodium sulfite (9.57 g) was added and the resulting slurry was allowedto stir at a temperature of about 25° C. for 30 min. The mixture wasextracted three times with ethyl acetate (50 mL for each extraction).The organic portions were combined, washed with brine, dried (Na₂SO₄),and concentrated under reduced pressure. The mixture was chromatographedby a silica gel chromatography column eluting with ethyl acetate(50%-100%)/hexanes to provide 0.75 g of product (2A for AD-mix α or 2Bfor AD-mix β) as a white solid (70% yield). ¹H NMR (400 MHz, CDCl₃) δ8.29 (1H, dd, J=0.44, 1.97 Hz), 7.87 (1H, dd, J=0.66, 2.19 Hz), 4.87(1H, m), 3.84 (1H, m), 3.66 (1H, m), 2.83 (1H, d, J=5.92 Hz), 2.11 (1H,t, J=5.92 Hz). LC/MS (M+1): 208.

As demonstrated above, the stereochemistry (R or S) of the resultingdiol, is dependent upon the chirality of the ligand used in the AD mixas described in Sharpless et al., J. Org. Chem. 57:2768-2771 (1992).AD-mix is composed of the following components: potassium osmate(K₂OsO₂(OH)₄), potassium ferricyanide (K₃Fe(CN)₆), potassium carbonate(K₂CO₃), and the chiral ligands are shown below

However, racemic diols can be synthesized by methods known in the art,using osmium tetroxide (OsO₄) and N-methyl morpholine N-oxide (NMO) inan aqueous acetone solution.

Intermediate 1 can be made from 2,3-dichloro-5-hydroxymethylpyridine 3via intermediate 4:

To a 500 mL round-bottom flask, manganese oxide (43.5 g, 0.50 mol) wasadded to a solution of 2,3-dichloro-5-hydroxylmethylpyridine (3, 8.10 g,50.0 mmol, Sigma-Aldrich, St. Louis, Mo.) in anhydrous CH₂Cl₂ (150 mL).The reaction mixture was stirred at a temperature of about 25° C. for 48h, filtered through CELITE, and concentrated under reduced pressure. Themixture was chromatographed by a silica gel chromatography columneluting with a gradient of ethyl acetate (0%-40%)/hexanes to provide 7.2g of 4 (90% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.08 (1H, s), 8.77 (1H,d, J=1.97 Hz), 8.25 (1H, d, J=1.97 Hz). LC/MS (M+1): 176.

To a stirred slurry of methyltriphenylphosphonium bromide (10.0 g) intoluene (200 mL) at 0° C. was added potassium t-butoxide (3.07 g)portionwise to produce a yellow slurry. After 1 hr, the reaction mixturewas cooled to −20° C. and 4 (4.0 grams, 22.72 mmol) dissolved intetrahydrofuran (6 mL) was added dropwise to produce a purple coloredslurry. The reaction mixture was heated to 0° C. and stirred for anadditional 1 hr. Then the reaction mixture was treated with saturatedaqueous brine (150 mL) and diluted with ethyl acetate (200 mL). Theresulting organic portion was washed with brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The resultingproduct was chromatographed by silica gel chromatography column elutingwith a gradient of ethyl acetate (0%-10%)/hexanes to provide 2.77 g of 1(70% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (1H, d, J=2.19 Hz), 7.80(1H, d, J=2.19 Hz), 6.63 (1H, dd, J=10.96, 17.80 Hz), 5.86 (1H, d,J=17.80 Hz), 5.45 (1H, d, J=10.96 Hz). LC/MS (M+1): 174.

5.2 Example 2 Alternative Stereoselective Synthesis of Aromatic, ChiralDiol Compounds

An alternative approach for preparing aromatic, chiral diol compounds isillustrated below, using as an example the synthesis of2,3-dichloro-5-vinyl-pyridine:

5,6-Dichloro-N-methoxy-N-methyl-nicotinamide (7)

To a well stirred suspension of 5,6-dichloronicotinic acid 5 (600 g,3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L)was added drop wise with stirring thionyl chloride (743.56 g, 6.25mole). The reaction mixture was set up for heating with reflux, fittedwith a gas trap filled with saturated aqueous sodium bicarbonate andheated at a temperature of 75° C. until the reaction mixture formed aclear solution, about 3 h. LC/MS of a sample quenched in methanol showedonly the presence of the methyl ester. The reaction mixture was cooledto a temperature of about 25° C. and concentrated under reduced pressureto provide 5,6-dichloronicotinoyl chloride 6 as a thick paste.

A suspension of N,O-dimethylhydroxylamine hydrochloride (350.53 g, 3.59mole, Sigma-Aldrich) in methylene chloride was cooled to 0° C. (internaltemp, dry ice/acetone bath), and triethyl amine (711.5 g, 7.03 mole) wasadded. The 5,6-dichloronicotinoyl chloride prepared above was dissolvedin methylene chloride (2.4 L) and added to the mixture at a rate suchthat the internal temperature did not exceed 15° C. After addition ofthe acid chloride, the reaction mixture was allowed to warm slowly to atemperature of about 25° C. overnight.

The reaction mixture was poured into 2 L of water, the aqueous andorganic portions were separated, and the aqueous portion was extractedtwice (500 mL per extraction) with methylene chloride. The combinedorganic portions were dried (MgSO₄) and concentrated under reducedpressure to provide a brown solid. The solid was then treated with 1 Lof boiling hexanes and heated at reflux for about 10 min. The resultingpale orange solution was decanted from the dark yellow-brown tar andallowed to cool. This step was repeated twice with the tar (500 mLboiling hexanes per step). The hexane mixtures were first allowed tocool to a temperature of about 25° C., then further cooled on ice/waterbaths. The resulting yellow needles were collected by vacuum filtrationand air dried to provide 730 g of the amide 7 (99% yield), which wassuitable to be carried on to the next step. ¹H NMR (400 MHz, CDCl₃) δ8.68 (m, 1H), 8.18 (m, 1H), 3.59 (OCH₃, 3H), 3.40 (NCH₃, 3H).

2-Propanol recrystallization of5,6-dichloro-N-methoxy-N-methyl-nicotinamide (7)

The procedure above was followed using 600 g of 5,6-dichloronicotinicacid 5 and keeping all other reagents and ratios the same until thecrude product was isolated. The crude product was dissolved in hot2-propanol, 1.4 mL/g, and allowed to cool slowly to a temperature ofabout 25° C. The resulting pale yellow solid was isolated by filtration,and the resulting supernatant was cooled to 0° C. to provide a secondcrop. The supernatant was subsequently reduced in volume byapproximately 70% and cooled to 0° C. to provide a slightly darkeryellow third crop that was identical by LC/MS to the first two crops.Overall, 730 g was isolated (97% yield).

Preparation of 1-(5,6-dichloro-pyridin-3-yl)-ethanone (8)

To a solution of 5,6-dichloro-N-methoxy-N-methyl-nicotinamide 7 (549 g,2.335 mole) in dry THF (2.335 L) cooled to −35° C. (internaltemperature, dry ice/acetone bath) was added slowly drop wise methylmagnesium chloride solution (913 g, 2.68 mole) at a rate such that theinternal temperature did not exceed −10° C. The reaction mixture wasallowed to stir for 3 h between −25° C. and −15° C., at which point analiquot was analyzed by LC/MS to insure the reaction had gone tocompletion.

The reaction mixture was poured into 2.3 L of 1N HCl. The aqueous andorganic portions were separated, the aqueous portion was washed twice(500 mL per wash) with diethyl ether, and the combined organic portionswere dried (MgSO₄) and concentrated under reduced pressure to provide apale yellow solid.

The solid was taken up in about 450 mL of hot 2-propanol. Upon cooling,the solution deposited pale yellow needles. The mixture was furthercooled (ice/water bath) and the resulting solid was collected by vacuumfiltration and air dried. The 2-propanol supernatant was concentrated toproduce an additional crop of needles. Total yield 431 g (97% yield). ¹HNMR (400 MHz, CDCl₃) δ 8.82 (m, 1H), 8.29 (m, 1H), 2.62 (COCH₃, 3H).

Preparation of 1-(5,6-Dichloro-pyridin-3-yl)-ethanol (9)

To a well stirred suspension of sodium borohydride (66.21 g, 1.75 mole)in methanol (3.5 L) cooled to 0° C. with a dry ice/acetone bath wasadded 1-(5,6-dichloro-pyridin-3-yl)-ethanone 8 (665 g, 3.5 mole) at arate such that the temperature remained at 0° C. After solid additionwas complete, the reaction mixture was stirred an additional 1 h, afterwhich time LC/MS analysis of an aliquot showed that the reaction wascomplete.

The methanol was removed under reduced pressure, and the residue wastaken up in 2 L diethyl ether and 2 L 1N HCl. The aqueous and organicportions were separated, the aqueous portion was extracted twice (250 mLper extraction) with ether, and the combined organic portions were dried(MgSO₄) and concentrated under reduced pressure to provide 670 g of apale yellow oil (99% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.20 (m, 1H),7.82 (m, 1H) 4.96 (m, 1H), 3.57 (s, 1H), 1.51 (d, J=6.5 Hz, 3H).

1-(5,6-Dichloro-pyridin-3-yl)-ethanol (9) hydrochloride salt

To a solution of 1-(5,6-dichloro-pyridin-3-yl)-ethanol 9 (200 g, 1.04mole) in ethyl acetate (200 mL) was added a solution of hydrogenchloride in dioxane/ethyl acetate prepared by diluting 4N HCl in dioxane(265 mL, 1.06 mole) in ethyl acetate (265 mL) with manual stirring.After a few minutes, a cream colored solid began to precipitate. Theresulting mixture was allowed to cool to a temperature of about 25° C.and was then further cooled in an ice/water bath. The solid was isolatedby vacuum filtration, washed with additional ethyl acetate (250 mL), andallowed to air dry for about 20 min. to provide 231 g of a solid (97%yield). This solid contained traces of ethyl acetate and was suitablefor further reaction without additional drying. ¹H NMR (400 MHz, CD₃OD)δ 8.36 (m, 1H), 8.03 (m, 1H) 4.92 (m, 1H), 1.47 (d, J=6.5 Hz, 3H).

Preparation of 2,3-Dichloro-5-vinyl-pyridine (1)

To a solution of 1-(5,6-dichloro-pyridin-3-yl)-ethanol 9 (311 g. 1.62mole) in chlorobenzene (3 L) was added p-toluene sulfonic acid (431 g,2.5 mole) and the reaction mixture was heated at reflux (about 140° C.)with concomitant removal of water. When the reaction was complete, themixture was concentrated to about 500 mL, diluted with 2 L water, andextracted with three times (1 L per extraction) ethyl acetate. Theorganic portions were combined, dried (Na₂SO₄), concentrated underreduced pressure with low heat, dissolved in 500 mL methylene chloride,and applied to the top of 2 kg silica column. The purified vinylpyridine was eluted with a 0% to 10% gradient of ethyl acetate inhexane. 178.55 g, of about 100% pure 2,3-dichloro-5-vinylpyridine wascollected as a clear oil which solidified upon cooling to 4° C. (63%yield). ¹H NMR (400 MHz, CDCl₃) δ 8.27 (m, 1H), 7.80 (dd, J=12, 18 Hz,1H), 6.62 (d, J=18 Hz, 1H), 5.46 (d, J=12 Hz, 1H).

5.3. Example 3 In Vivo Assays for Prevention or Treatment of Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a compound offormula I when food is removed for 16 hours before dosing. A controlgroup acts as a comparison to rats treated with a compound of formula I.The control group is administered the carrier for the compound offormula I. The volume of carrier administered to the control group isthe same as the volume of carrier and compound of formula I administeredto the test group.

Acute Pain:

To assess the actions of the compounds of formula I on the treatment orprevention of acute pain the rat tail flick test can be used. Rats aregently restrained by hand and the tail exposed to a focused beam ofradiant heat at a point 5 cm from the tip using a tail flick unit (Model7360, commercially available from Ugo Basile of Italy). Tail flicklatencies are as defined as the interval between the onset of thethermal stimulus and the flick of the tail. Animals not respondingwithin 20 seconds are removed from the tail flick unit and assigned awithdrawal latency of 20 seconds. Tail flick latencies are measuredimmediately before (pre-treatment) and 1, 3, and 5 hours followingadministration of a compound of formula I. Data are expressed as tailflick latency(s) and the percentage of the maximal possible effect (%MPE), i.e., 20 seconds, is calculated as follows:

${\%\mspace{14mu}{MPE}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu}{administration}{\mspace{11mu}\;}{latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{latency}} \right)} \right\rbrack}{\left( {20\mspace{14mu} s\mspace{14mu}{pre}\text{-}{administration}{\mspace{11mu}\;}{latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Inflammatory Pain:

To assess the actions of the compounds of formula I on the treatment orprevention of inflammatory pain the Freund's complete adjuvant (“FCA”)model of inflammatory pain can be used. FCA-induced inflammation of therat hind paw is associated with the development of persistentinflammatory mechanical and thermal hyperalgesia and provides reliableprediction of the anti-hyperalgesic action of clinically usefulanalgesic drugs (L. Bartho et al., “Involvement of Capsaicin-sensitiveNeurones in Hyperalgesia and Enhanced Opioid Antinociception inInflammation,” Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670(1990)). The left hind paw of each animal is administered a 50 μLintraplantar injection of 50% FCA. 24 hour post injection, the animal isassessed for response to noxious mechanical stimuli by determining thepaw withdrawal threshold (“PWT”), or to noxious thermal stimuli bydetermining the paw withdrawal latencies (“PWL”), as described below.Rats may then be administered a single injection of 1, 3, 10 or 30 mg/kgof either a compound of formula I; 30 mg/kg of a control selected fromcelecoxib, indomethacin or naproxen; or carrier. Responses to noxiousmechanical or thermal stimuli are determined 1, 3, 5 and 24 hours postadministration. Percentage reversal of hyperalgesia for each animal isdefined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\left\lbrack {\left( {{post}{\mspace{11mu}\;}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} \right) - \mspace{14mu}\left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}\mspace{14mu}{or}\mspace{14mu}{PWL}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}\mspace{14mu}{or}{\mspace{11mu}\;}{PWL}} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of the compounds of formula I for the treatment orprevention of neuropathic pain either the Seltzer model or the Chungmodel can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.Percentage reversal of neuropathic hyperalgesia is defined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\left\lbrack {\left( {{post}{\mspace{11mu}\;}{administration}\mspace{14mu}{PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic paincan be used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is isolatedand tightly ligated with silk thread. A complete hemostasis is confirmedand the wound is sutured using non-absorbable sutures, such as nylonsutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then be returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after administration a compound of formula Ifor the left rear paw of the animal. The animal can also be assessed forresponse to noxious thermal stimuli or for tactile allodynia, asdescribed below. The Chung model for neuropathic pain is described in S.H. Kim, “An Experimental Model for Peripheral Neuropathy Produced bySegmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdetermined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind PWLs to a noxious thermal stimulus are determined using aplantar test apparatus (commercially available from Ugo Basile of Italy)following the technique described by K. Hargreaves et al., “A New andSensitive Method for Measuring Thermal Nociception in CutaneousHyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposure time is setat 32 seconds to avoid tissue damage and any directed paw withdrawalfrom the heat source is taken as the end point. Three latencies aredetermined at each time point and averaged. Only the affected(ipsilateral) paw is tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats can be placed in clear, Plexiglascompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the left(operated) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

Capsaicin-Induced Eve Wipe Test:

To assess the effect of compounds of formula I on TRPV1receptor-mediated pain, the capsaicin-induced eye wipe test can be used(N. R. Gavva et al., “AMG 9810[(E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide],a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with AntihyperalgesicProperties”, J. Pharmacol. Exp. Ther. 313:474-484 (2005)). The eye wipetest is a reliable high-throughput test of the effect of TRPV1antagonists. Rats can be given a single injection of 1, 3, 10 or 30mg/kg of either a compound of formula I; 30 mg/kg of a control selectedfrom celecoxib, indomethacin or naproxen; or carrier. At 1, 3 or 5 hoursafter drug administration, 3 μL of a 100 μM capsaicin solution (in 10%EtOH/PBS) is instilled in one eye of each animal with a pipette. Thenumber of forelimb movements (touching or wiping of thecapsaicin-treated eye) are counted during a 2 minute period followinginstillation of capsaicin into the eye.

5.4. Example 4 Binding of Compounds of Formula I to TRPV1

Methods for assaying compounds capable of inhibiting TRPV1 are known inthe art, for example, those methods disclosed in U.S. Pat. No. 6,239,267to Duckworth et al., U.S. Pat. No. 6,406,908 to Mc Intyre et al., orU.S. Pat. No. 6,335,180 to Julius et al.

Protocol 1

Human TRPV1 Cloning:

Human spinal cord RNA (commercially available from Clontech, Palo Alto,Calif.) is used. Reverse transcription is conducted on 1.0 μg total RNAusing Thermoscript Reverse Transcriptase (commercially available fromInvitrogen, Carlsbad, Calif.) and oligo dT primers as detailed in itsproduct description. Reverse transcription reactions are incubated at55° C. for 1 h, heat-inactivated at 85° C. for 5 min, and RNaseH-treated at 37° C. for 20 min.

Human TRPV1 cDNA sequence is obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences are removed and flanking exonic sequences are joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human TRPV1 are designed as follows: forward primer,5′-GAAGATCTTCGCTGGTTGCACACTGGGCCACA-3′ (SEQ ID NO: 1); and reverseprimer, 5′-GAAGATCTTCGGGGACAGTGACGGTTGGATGT-3′ (SEQ ID NO: 2).

Using these primers, PCR of TRPV1 is performed on one tenth of theReverse transcription reaction mixture using Expand Long TemplatePolymerase and Expand Buffer 2 in a final volume of 50 μL according tothe manufacturer's instructions (Roche Applied Sciences, Indianapolis,Ind.). After denaturation at 94° C. for 2 min PCR amplification isperformed for 25 cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68°C. for 3 min followed by a final incubation at 72° C. for 7 min tocomplete the amplification. The PCR product of about 2.8 kb isgel-isolated using a 1.0% agarose, Tris-Acetate gel containing 1.6 μg/mLof crystal violet and purified with a S.N.A.P. UV-Free Gel PurificationKit (commercially available from Invitrogen). The TRPV1 PCR product iscloned into the pIND/V5-His-TOPO vector (commercially available fromInvitrogen) according to the manufacturer's instructions to result inthe TRPV1-pIND construct. DNA preparations, restriction enzymedigestions, and preliminary DNA sequencing are performed according tostandard protocols. Full-length sequencing confirms the identity of thehuman TRPV1.

Generation of Inducible Cell Lines:

Unless noted otherwise, cell culture reagents are purchased from LifeTechnologies of Rockville, Md. HEK293-EcR cells expressing the ecdysonereceptor (commercially available from Invitrogen) are cultured in GrowthMedium (Dulbecco's Modified Eagles Medium containing 10% fetal bovineserum (commercially available from HYCLONE, Logan, Utah), 1×penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400μg/mL Zeocin (commercially available from Invitrogen)). The TRPV1-pINDconstructs are transfected into the HEK293-EcR cell line using Fugenetransfection reagent (commercially available from Roche AppliedSciences, Basel, Switzerland). After 48 h, cells are transferred toSelection Medium (Growth Medium containing 300 μg/mL G418 (commerciallyavailable from Invitrogen)). Approximately 3 weeks later individualZeocin/G418 resistant colonies are isolated and expanded. To identifyfunctional clones, multiple colonies are plated into 96-well plates andexpression is induced for 48 h using Selection Medium supplemented with5 μM ponasterone A (“PonA”) (commercially available from Invitrogen). Onthe day of assay, cells are loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx is measured using a Fluorescence ImagingPlate Reader (“FLIPR”) as described below. Functional clones arere-assayed, expanded, and cryopreserved.

pH-Based Assay:

Two days prior to performing this assay, cells are seeded onpoly-D-lysine-coated 96-well clear-bottom black plates (commerciallyavailable from Becton-Dickinson) at 75,000 cells/well in growth mediacontaining 5 μM PonA (commercially available from Invitrogen) to induceexpression of TRPV1. On the day of the assay, the plates are washed with0.2 mL 1× Hank's Balanced Salt Solution (commercially available fromLife Technologies) containing 1.6 mM CaCl₂ and 20 mM HEPES, pH 7.4(“wash buffer”), and loaded using 0.1 mL of wash buffer containingFluo-4 (3 μM final concentration, commercially available from MolecularProbes). After 1 h, the cells are washed twice with 0.2 mL wash bufferand resuspended in 0.05 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 3.5 mM CaCl₂and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates are then transferredto a FLIPR for assay. The test compound is to be diluted in assaybuffer, and 50 μL of the resultant solution can be added to the cellplates and the solution is monitored for two minutes. The finalconcentration of the test compound is to be adjusted to range from about50 picoM to about 3 μM. Agonist buffer (wash buffer titrated with 1N HClto provide a solution having a pH of 5.5 when mixed 1:1 with assaybuffer) (0.1 mL) is then to be added to each well, and the plates are tobe incubated for 1 additional minute. Data will be collected over theentire time course and analyzed using Excel and Graph Pad Prism todetermine the IC₅₀.

Capsaicin-Based Assay:

Two days prior to performing this assay, cells are seeded inpoly-D-lysine-coated 96-well clear-bottom black plates (50,000cells/well) in growth media containing 5 μM PonA (commercially availablefrom Invitrogen) to induce expression of TRPV1. On the day of the assay,the plates are washed with 0.2 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 1 mM CaCl₂and 20 mM HEPES, pH 7.4, and cells are loaded using 0.1 mL of washbuffer containing Fluo-4 (3 μM final). After one hour, the cells arewashed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL ofwash buffer. The plates are transferred to a FLIPR for assay. 50 μL oftest compound diluted with assay buffer (1× Hank's Balanced SaltSolution containing 1 mM CaCl₂ and 20 mM HEPES, pH 7.4) are added to thecell plates and incubated for 2 min. The final concentration of thecompound is to be adjusted to range from about 50 picoM to about 3 μM.Human TRPV1 is to be activated by the addition of 50 μL of capsaicin(400 nM), and the plates are to be incubated for an additional 3 min.Data will be collected over the entire time course and analyzed usingExcel and GraphPad Prism to determine the IC₅₀.

Protocol 2

For Protocol 2, a Chinese Hamster Ovary cell line (CHO) that has beenengineered to constitutively express human recombinant TRPV1 is to beused (TRPV1/CHO cells). The TRPV1/CHO cell line can be generated asdescribed below.

Human TRPV1 Cloning:

A cDNA for the human TRPV1 receptor (hTRPV1) is amplified by PCR(KOD-Plus DNA polymerase, ToYoBo, Japan) from a human brain cDNA library(BioChain) using primers designed surrounding the complete hTRPV1 openreading frame as follows: forward primer,5′-GGATCCAGCAAGGATGAAGAAATGG-3′ (SEQ ID NO: 3), and reverse primer,5′-TGTCTGCGTGACGTCCTCACTTCT-3′ (SEQ ID NO: 4). The resulting PCRproducts are purified from agarose gels using Gel Band Purification Kit(GE Healthcare Bioscience) and are subcloned into pCR-Blunt vector(Invitrogen). The cloned cDNA is fully sequenced using a fluorescentdye-terminator reagent (BigDye Terminator ver3.1 Cycle Sequencing Kit,Applied Biosystems) and ABI Prism 3100 genetic analyzer (AppliedBiosystems). The pCR-Blunt vector containing the hTRPV1 cDNA issubjected to restriction digestion with EcoR1. The restriction fragmentis subcloned into expression vector pcDNA3.1(−) (Invitrogen) and namedpcDNA3.1(−)-hVR1 plasmid. The sequence of the cDNA encoding TRPV1 isavailable at GenBank accession number AJ277028.

Generation of the TRPV1/CHO Cell Line:

CHO-K1 cells are maintained in growth medium consisting of α-MEM, 10%FBS (Hyclone), and 100 IU/mL of penicillin-100 μg/mL of streptomycinmixed solution (Nacalai Tesque, Japan) at 37° C. in an environment ofhumidified 95% air and 5% CO₂. The cells are transfected with thepcDNA3.1(−)-hVR1 plasmid using FuGENE6 (Roche) according to themanufacturer's protocol. 24 hr after transfection, neomycin-resistantcells are selected using 1 mg/mL G418 (Nacalai Tesque). After 2 weeks,individual colonies can be picked, expanded, and screened for theexpression of hTRPV1 in the capsaicin-induced Ca²⁺ influx assay (seebelow) with a FLIPR (Molecular Devices). A clone with the largest Ca²⁺response to capsaicin should be selected and re-cloned by the sameprocedure. The cells expressing hTRPV1 are cultured in the growth mediumsupplemented with 1 mg/mL G418. Approximately 1 month later, stableexpression of functional TRPV1 receptors in the selected cell line is tobe confirmed by validating Ca²⁺ responses with or without capsazepine(Sigma, at 1 nM-10 μM) in capsaicin assay.

Capsaicin-Induced Ca²⁺ Influx Assay for Cell Selection:

The following assay can be performed to identify cells with hTRPV1expression. CHO-K1 cells transfected with pcDNA3.1(−)-hVR1 plasmid areseeded in 384-well black-wall clear-bottom plates (Corning) andcultivated in growth medium (see above) for 1 day. On the day ofexperiment, culture medium is exchanged to assay buffer (20 mM HEPES,137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose,2.5 mM probenecid, pH 7.4) containing 4 μM Fluo-3-AM (Dojin, Japan).After the incubation at 37° C. for 1 hr, each well is washed 3 timeswith assay buffer using an EMBLA 384 plate washer (Molecular Devices)and refilled with assay buffer. The plates are incubated at atemperature of about 25° C. for 10 min. Subsequently, the plates areinserted into a FLIPR, and 1.5 μM capsaicin (Sigma) solution prepared inassay buffer is added to each well (final concentration is 500 nM).Cellular responses are monitored for 5 min.

Cell Culture:

1. Cell Culture Media

1. Alpha-MEM (Gibco, CAT: 12561-056, LOT: 1285752): 450 mL.

2. Fetal Bovine Serum (FBS), heat inactivated (Gibco, CAT: 16140-071,LOT: 1276457): 50 mL.

3. HEPES Buffer Solution, 1M stock (Gibco, CAT: 15630-080): 10 mL (final20 mM).

4. Geneticin, 50 mg/mL stock (Gibco, CAT: 10135-035): 10 mL (final 1mg/mL).

5. Antimicotic Antibiotic Mixed Solution, 100× stock (Nacalai Tesque,Japan, CAT: 02892-54): 5 mL.

Components 1-5 above are combined at the indicated amounts and stored at4° C. The cell culture media are brought to about 37° C. before use.Optionally, component 5 can be replaced by penicillin-streptomycinsolution (for example, Gibco 15140-122 or Sigma P-0781).

2. Thawing the Cells

TRPV1/CHO cells are frozen in Cellbanker™ (Juji-Field Inc., Japan, CAT:BLC-1) and stored at −80° C. Optimized cryopreservation solutioncontaining dimethyl sulphoxide and FBS can be used.

Vials containing the TRPV1/CHO cells are stored at −80° C. After removalfrom −80° C., the vial is immediately transferred to a 37° C. water bathto thaw for ca. 1-2 minutes. Once completely thawed, the contents of thevial (1 mL/vial) are transferred to a sterile 15 mL test tube and 9 mLwarm culture media are slowly added. The test tube is subsequentlycentrifuged at 1000 rpm for 4 min at a temperature of about 25° C. Thesupernatant is removed and the pellet resuspended in 10 mL of culturemedia. The cell suspension is transferred to a sterile 75 cm² plasticflask and incubated at humidified 5% CO₂/95% air at 37° C. To monitorviability, the cells are visually inspected and/or counted, beginning atapproximately 1 hr after incubation.

3. Passaging the Cells

The cells in a flask are close to confluence at the time of passaging.Cell culture media can be removed from the culture flask and 10 mL ofsterile PBS(−), added and the flask gently shaken. The PBS is removedfrom the flask and 2 mL of trypsin/EDTA solution (0.05% trypsin withEDTA-4Na; Gibco, CAT: 25300-054) is added and the flask gently shaken.The flask is incubated at 37° C. for about 2 min. 8 mL cell culturemedia are subsequently added to the flask and the flask shaken to ensurethat all cells are in solution. The cell suspension is then transferredto a sterile 15 mL or 50 mL plastic tube, centrifuged at 1,000 rpm for 4min at a temperature of about 25° C. The supernatant is removed and thepellet resuspended in ca. 5 mL of culture media. The cell count ismeasured using the Burker-Turk hemocytometer.

The cells are seeded into a sterile 75 cm² plastic flask in ca. 0.8×10⁵cells/mL for 72 hr and incubated in humidified 5% CO₂/95% air at 37° C.

4. Freezing the Cells

The procedure up to the measurement of the cell count is the same as inthe section Passaging the Cells above. Subsequently, the cell suspensioncan be centrifuged at 1,000 rpm for 4 min at a temperature of about 25°C. The supernatant can be removed and the pellet resuspended inCellbanker™ solution to get a final concentration of from 5×10⁵ to 5×10⁶cells/mL. The cell suspension can be transferred into appropriatelylabeled 1 mL cryovials and then placed into the −80° C. freezer.

pH-Based Assay:

The following assay can be conducted to determine the concentration ofsulfuric acid that would give rise to a pH that induces a Ca²⁺ responseoptimal to test compounds for their effect on TRPV1.

1. Cells

TRPV1/CHO cells can be seeded in the 96-well clear-bottom black-wallplate (Nunc) at densities of 1-2×10⁴ cells/well and grown in 100 μL ofculture medium (alpha-MEM supplemented with 10% FBS, 20 mM HEPES, 1mg/mL geneticin and 1% antibiotic-antimycotic mixed stock solution) for1-2 days before the experiment.

2. Determination of pH Sensitivity and Agonist Dose

2.1. Agonist Solution

Different agonist solutions with sulfuric acid concentrations of from 15mM to 18 mM can be prepared by diluting 1M sulfuric acid with measuringbuffer. The different sulfuric acid concentrations in the agonistsolutions can be selected such that a 1:4 dilution would result in afinal sulfuric acid concentration of between 3.0 mM to 3.6 mM,respectively.

2.2. Assay

Ca²⁺ influx into TRPV1/CHO cells in response to low pH as measured byFura-2 AM fluorescence is measured. The cells can be stimulated using3.0 mM (well number B1-6), 3.1 mM (C1-6), 3.2 mM (D1-6), 3.3 mM (E1-6),3.4 mM (F1-6), 3.5 mM (G1-6), or 3.6 mM (H1-6) H₂S(═O)₄ or pH 7.2measuring buffer without H₂S(═O)₄ (A1-6).

(1) Culture medium can be removed using an 8-channel-pipette (Rainin,USA) from the 96-well plate and the wells can be refilled with 100 μL,of loading buffer (20 mM HEPES, 115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂,1.8 mM CaCl₂, 13.8 mM D-glucose, 2.5 mM probenecid, pH 7.4) containing 5μM Fura-2 AM (Dojin, Japan).

(2) The 96-well plate can be incubated at 37° C. for 45 min.

(3) The loading buffer can be removed from each well. The cells can besubsequently washed twice with 150 μL of measuring buffer (20 mM HEPES,115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂, 5.0 mM CaCl₂, 13.8 mM D-glucose,0.1% BSA, pH 7.4) (no probenecid). The wells can then be refilled with80 μL of measuring buffer.

(4) After an incubation at 4° C. for 15 min, the 96-well plate can betransferred to FDSS-3000 (Hamamatsu Photonics, Japan).

(5) The Fura-2 fluorescent intensity can be monitored at a wavelength of340 nm and at 380 nm, respectively, at a rate of 0.5 Hz for a total of240 seconds. After 16 time points (32 sec) of baseline detection, 20 μLof agonist solution can be added to each well. The final volume is 100μL/well.

(6) Fluorescence intensity ratio refers to the fluorescence intensity at340 nm over the fluorescence intensity at 380 nm at a particular timepoint. The baseline can be set as the average of the fluorescentintensity ratios for the first 16 time points before the addition ofagonist solution. The maximum response is the highest fluorescentintensity ratio during the 60 time points following addition of agonistsolution.

(7) Maximal signal ratios from each well can be calculated as outputdata using the FDSS-3000 analysis program. Data is analyzed using Excel(Microsoft) and XLfit (idbs) software.

2.3. pH Determination

After the observation of Ca²⁺ responses, the buffer of each lane (50μL/well, 8-20 wells/plate) can be collected well by well and the pHvalues are measured using a portable pH meter (Shindengen, Japan).

Lanes optimal for testing the effects of the compounds on the TRPV1calcium channel are selected. The final sulfuric acid concentrations inthe wells of these lanes can be 3.2 mM and 3.3 mM, respectively. Thesefinal sulfuric acid concentrations can be obtained using agonistsolutions with 16.0 mM and 16.5 mM sulfuric acid concentrations,respectively. The pH obtained using these sulfuric acid concentrationsis ca. 5.0-5.1.

Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acidconcentrations, respectively, can be selected for the experimentsdescribed below in section 3.

3. pH Assay

3.1. Agonist

Two different agonist solutions with different H₂S(═O)₄ concentrationscan be used for the pH assay. For one half of a 96-well plate oneagonist solution can be used, for the other half the other agonistsolution. The agonist solutions can be obtained by diluting sulfuricacid (H₂S(═O)₄, 1M) with measuring buffer. The concentrations for thetwo agonist solutions can be determined as described above in Section 2of Protocol 2.

The sulfuric acid concentrations between the two agonist solutions maydiffer by 0.5 mM. In the experiment described in Section 2 of Protocol2, the sulfuric acid concentrations in the agonist solutions can bedetermined to be 16 mM and 16.5 mM, respectively. After 1:4 dilution ofthe agonist solutions, the final sulfuric acid concentration can be 3.2mM and 3.3 mM, respectively. The resulting pH value for the pH assay is5.0 to 5.1.

3.2. Test Compounds

Test compounds are dissolved in DMSO to yield 1 mM stock solutions. Thestock solutions are further diluted using DMSO in 1:3 serial dilutionsteps with 6 points (1000 μM, 250 μM, 62.5 μM, 15.625 μM, 3.9062 μM and0.977 μM). The thereby-obtained solutions are further diluted inmeasuring buffer (1:100) as 10× stock serial dilutions with a DMSOconcentration of 1%. 10 μL of a 10× stock is added into each well atstep 3.3.(4) of Protocol 2. Thus, the final concentrations ofantagonists ranges from 1000-0.977 nM containing 0.1% DMSO.

3.3. Assay

Steps (1) and (2) of this Assay can be the same as steps 2.2.(1) and2.2.(2) of Protocol 2, respectively.

(3) The cells can be washed twice with 150 μL of measuring buffer(mentioned in 2.2.(3) of Protocol 2, no probenecid). The wells can besubsequently refilled with 70 μL of measuring buffer.

(4) Either 10 μL of measuring buffer or 10 μL of 10× stock serialdilution of test compound (described in 3.2. above) can be applied toeach well. Usually, only one test compound can be tested per 96-wellplate. The number of replicates per 96-well plate for a particularantagonist at a particular concentration is 7×2 since two differentsulfuric acid concentrations can be used per 96-well plate (N=7×2).

Step (5) is the same as 2.2.(4) above.

(6) Fura-2 fluorescent intensity can be monitored as described in2.2.(5) above. After 16 time points of baseline detection, 20 μL ofagonist solution (measuring buffer titrated with H₂S(═O)₄ to yield pH5.0-5.1 when mixed 1:4 with the measuring buffer containing testcompound) can be added to each well (final volume 100 μL/well).

Steps (7) and (8) are as described in 2.2.(6) and 2.2.(7) above,respectively.

3.4. pH Check

(1) The pH values of the buffer in the wells of A1→H1 and A7→H7(longitudinally) can be measured one by one using a portable pH meter.

(2) When a well is confirmed as pH 5.0 or 5.1, the next five wells toits right are checked one after another.

(3) For IC₅₀ calculation, only the data from wells with pH values of5.0-5.1 are to be used.

The number of wells tested for their pH varies among plates (about 16-60wells/plate). The number depends on the results of 3.4.(1) above and theCa²⁺ responses.

Capsaicin-Based Assay:

One day prior to assay, TRPV1/CHO cells are seeded in 96-wellclear-bottom black plates (20,000 cells/well) in growth media. On theday of the experiment, the cells are washed with 0.2 mL 1× Hank'sBalanced Salt Solution (Life Technologies) containing 1.6 mM CaCl₂ and20 mM HEPES, pH 7.4 (“wash buffer”). Subsequently, the cells are to beloaded by incubation in 0.1 mL of wash buffer containing Fluo-4 at 3 μMfinal concentration. After 1 hour, the cells can be washed twice with0.2 mL wash buffer and resuspended in 0.1 mL wash buffer. The plates canthen be transferred to a Fluorescence Imaging Plate Reader (MolecularDevices). Fluorescence intensity is monitored for 15 seconds toestablish a baseline. Subsequently, test compounds diluted in assaybuffer (1× Hank's Balanced Salt Solution containing 1 mM CaCl₂ and 20 mMHEPES, pH 7.4) containing 1% DMSO can be added to the cell plate andfluorescence is monitored for 2 minutes. The final concentration of thecompound is adjusted to range from 100 μM to 1.5625 μM. If the testcompound are an especially potent antagonist, the final concentration ofthe compound is to be adjusted to range from 10 μM to 1.5625 nM. HumanTRPV1 can then be activated by the addition of 50 μL capsaicin (100 nMfinal concentration) and plates incubated for an additional 3 min. Datais collected over the entire time course and analyzed using Excel andthe curve-fitting formula GraphPad Prism.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples which are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those in the art and are intended to fallwithin the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

What is claimed:
 1. A compound with a formula selected from:

or a pharmaceutically acceptable salt thereof, wherein Ar₂ is:

R₁ is -halo, —(C₁-C₄)alkyl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); R₃ is—H or —(C₁-C₆)alkyl; each R₁₄ is independently -halo, —(C₁-C₆)alkyl,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); q is the integer 0, 1, 2, 3, or 4;and s is the integer 0, 1, 2, 3, 4, or
 5. 2. The compound of claim 1,wherein each R₃ is —H.
 3. The compound of claim 1, wherein at least oneR₃ is —(C₁-C₆)alkyl.
 4. A composition comprising a compound of claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 5. A compound which is:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, which is:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim5, which is:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein Ar₂ is:


9. The compound of claim 8, wherein at least one R₁₄ is -halo or—C(halo)₃.
 10. The compound of claim 8, wherein s is 1 or
 2. 11. Thecompound of claim 10, wherein Ar₂ is:


12. The compound of claim 1, wherein Ar₂ is:


13. The compound of claim 12, wherein at least one R₁₄ is -halo or—C(halo)₃.
 14. The compound of claim 12, wherein q is 1 or
 2. 15. Thecompound of claim 14, wherein Ar₂ is:


16. The compound of claim 1, wherein R₁ is -halo.
 17. The compound ofclaim 1, wherein R₁ is —C(halo)₃.
 18. The compound of claim 1, whereinthe compound is a pharmaceutically acceptable salt.
 19. The compound ofclaim 1, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1, wherein the compound has the formula:

or a pharmaceutically acceptable salt thereof.
 24. A compound which is: